3-Azabicyclo[3.1.0]hexane derivatives useful in therapy

ABSTRACT

Compounds of formula I,  
                 
 
     where the substituents are as defined herein, and the pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof, are pharmaceutically and veterinarily useful, in particular they bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). They are likely to be useful in the treatment of diseases or conditions modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; pruritic dermatoses, such as allergic dermatitis and atopy; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage; and head trauma.

[0001] This claims application claims priority under 35 U.S.C. 120 ofU.S. Ser. No. 09/883,567, filed Jun. 18, 2001.

[0002] This invention relates to pharmaceutically useful compounds, inparticular compounds that bind to opiate receptors (e.g. mu, kappa anddelta opioid receptors). Compounds that bind to such receptors arelikely to be useful in the treatment of diseases modulated by opiatereceptors, for example irritable bowel syndrome; constipation; nausea;vomiting; and pruritic dermatoses, such as allergic dermatitis and atopyin animals and humans. Compounds that bind to opiate receptors have alsobeen indicated in the treatment of eating disorders, opiate overdoses,depression, smoking and alcohol addiction, sexual dysfunction, shock,stroke, spinal damage and head trauma.

[0003] There is a particular need for an improved treatment of itching.Itching, or pruritus, is a common dermatological symptom that can giverise to considerable distress in both humans and animals. Pruritus isoften associated with inflammatory skin diseases which may be caused byhypersensitivity reactions, including reactions to insect bites, such asflea bites, and to environmental allergens, such as house dust mite orpollen; by bacterial and fungal infections of the skin; or byectoparasite infections.

[0004] Existing treatments that have been employed in the treatment ofpruritus include the use of corticosteroids and antihistamines. However,both of these treatments are known to have undesirable side effects.Other therapies that have been employed include the use of essentialfatty acid dietary supplements, though these have the disadvantages ofbeing slow to act, and of offering only limited efficacy againstallergic dermatitis. A variety of emollients such as soft paraffin,glycerine and lanolin are also employed, but with limited success.

[0005] Thus, there is a continuing need for alternative and/or improvedtreatments of pruritus.

[0006] Certain 4-arylpiperidine-based compounds are disclosed in interalia European patent applications EP 287339, EP 506468 and EP 506478 asopioid antagonists. In addition, International Patent Application WO95/15327 discloses azabicycloalkane derivatives useful as neurolepticagents.

[0007] International Patent Application WO00/39089, filed before thepriority date of the instant application, but published thereafter, isherein incorporated by reference in its entirety, and disclosesazabicycloalkanes of similar structure to those described herein below,with different R⁴ groups.

[0008] According to the invention there is provided a compound offormula I,

[0009] wherein the “Ar” ring represents an optionally benzo-fused phenylor 5- or 6-membered heteroaryl ring;

[0010] R¹ when taken alone is H, halogen, NO₂, NH₂, NY²WY¹, Het¹, AD,CO₂R⁷, C(O)R⁸, C(═NOH)R⁸, or OE,

[0011] Y² is H, C₁₋₆ alkyl, C₃₋₆ alkenyl (each of which alkyl andalkenyl is optionally substituted by aryl, aryloxy or Het¹),

[0012] W is SO₂, CO, C(O)O, P(Y¹)═O, P(Y¹)═S,

[0013] Y¹ is C₁₋₁₀ alkyl (optionally substituted by one or moresubstituents independently selected from halogen, OH, C₁₋₄ alkoxy, C₁₋₆alkanoyloxy, CONH₂, C₁₋₆ alkoxycarbonyl, NH₂, aryl, mono- or di(C₁₋₄alkyl)amino, C₃₋₈ cycloalkyl, phthalimidyl, Het¹), Het¹, aryl(optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and halogen), NH₂, N(C₁₋₆alkyl)₂ or NH(C₁₋₆ alkyl),

[0014] Het¹ is a heterocyclic group containing up to 4 heteroatomsselected from N, O and S, which may comprise up to 3 rings (preferably aheteroaryl group, optionally benzo- or pyrido-fused heteroaryl),optionally substituted by one or more substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₃₋₆ halocycloalkyl, ═O, OH, halogen, NO₂,SiR^(19a)R^(19b)R^(19c), CON^(20a)R^(20b), NR^(20a)R^(20b), SR^(21a),NR^(21b)SO₂R^(22a), NR^(21c)C(O)OR^(22b), NR^(21d)COR^(22d), and C₁₋₆alkoxycarbonyl,

[0015] and if a S atom is present in a ring, it can be present as partof a —S—, S(O)— or —S(O₂)— group, and carbon atoms in the ring can bepresent as a part of a carbonyl moiety;

[0016] R^(19a), R^(19b), R^(19c) each independently represent C₁₋₆ alkylor aryl,

[0017] R^(20a) and R^(20b) each independently represent H, C₁₋₆ alkyl,aryl, (C₁₋₄ alkyl)phenyl, each of which alkyl, aryl and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,NH₂ and/or halogen,

[0018] or R^(20a) and R^(20b) can be taken together with the N atom towhich they are attached, to form a 4- to 6-membered ring optionallysubstituted by one or more substitutuents independently selected fromone or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, ═O, NO₂, NH₂ and/or halogen,

[0019] R^(21a, b, c and d) each independently represent H, C₁₋₆ alkyl,aryl or C₁₋₄ alkylphenyl, each of which alkyl, aryl, and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,halogen, NH₂,

[0020] R^(22a, b and c) each independently represent C₁₋₆ alkyl, aryl orC₁₋₄ alkylphenyl, each of which alkyl, aryl, and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,halogen, NH₂,

[0021] A is C₁₋₄ alkylene, C₂₋₄ alkenylene or C₂₋₄ alkynylene, each ofwhich is optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen and/or OH,

[0022] D is H, OH, CN, NR²⁵R²⁶, CONR²⁵R²⁶, NHR²⁷, CO₂R²⁸, COR²⁹,C(═NOR)R²⁹,

[0023] or AD is CN, NR²⁵R²⁶, CONR²⁵R²⁶,

[0024] where R²⁵ and R²⁸ are either each independently H, C₁₋₃ alkyl,C₃₋₈ cycloalkyl, aryl, C₁₋₄ alkylphenyl (each of which C₁₋₃ alkyl, C₃₋₈cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionally substituted by oneor more NO₂, halogen, C₁₋₄ alkyl and/or C₁₋₄ alkoxy, (each of whichlatter C₁₋₄ alkyl and C₁₋₄ alkoxy is optionally substituted by one ormore halogen)),

[0025] or R²⁵ and R²⁶ are taken together with the N atom to which theyare attached and can form a 4- to 7-membered heterocyclic ringoptionally incorporating one or more further hetero atoms selected fromN, O and S, and which ring is optionally substituted by one or more C₁₋₄alkyl, OH, ═O, NO₂, NH₂ and/or halogen,

[0026] R²⁷ is COR³⁰, CO₂R^(31a), SO₂R^(31b),

[0027] R²⁸ and R²⁹ are each independently H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl or C₁₋₄alkylphenyl, each of which C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionally substituted by oneor more NO₂, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy (each of which latter C₁₋₄alkyl and C₁₋₄ alkoxy are optionally substituted by one or morehalogen),

[0028] R³⁰ is H, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈cycloalkyloxy, aryl, aryloxy, C₁₋₄ alkylphenyl, phenyl(C₁₋₄)alkoxy,(each of which C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈cycloalkyloxy, aryl, aryloxy, C₁₋₄ alkylphenyl and phenyl(C₁₋₄)alkoxyare optionally substituted by one or more NO₂, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy (which latter alkyl and alkoxy are optionally substituted by oneor more halogen)),

[0029] R^(31a) and R^(31b) are each independently C₁₋₄ alkyl, C₃₋₈cycloalkyl, aryl or C₁₋₄ alkylphenyl, each of which is optionallysubstituted by one or more NO₂, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy, eachof which latter alkyl and alkoxy is optionally substituted by one morehalogen

[0030] E is H, CONR³²R³³, CSNR³²R³³, COR³⁴, CO₂R³⁴, COCH(R^(34a))NH₂,R³⁵, CH₂CO₂R^(35a), CHR^(35b)CO₂R^(35a), CH₂OCO₂R^(35c),CHR^(35d)OCO₂R^(35c), COCR³⁶═CR³⁷NH₂, COCHR³⁶CHR³⁷NH₂, or PO(OR³⁸)₂,

[0031] R³² and R³³ are each independently H, C₃₋₁₀ alkylalkenyl, C₃₋₇cycloalkyl (optionally substituted by C₁₋₄ alkyl), phenyl (optionallysubstituted by (X)_(n)), C₁₋₁₀ alkyl (optionally substituted by C₄₋₇cycloalkyl (optionally substituted by C₁₋₄ alkyl) or phenyl optionallysubstituted by (X)_(n)),

[0032] or R³² and R³³ can be taken together with the N atom to whichthey are attached and can form a 5- to 8-membered heterocycle optionallycomprising further hetero atoms selected from N, O and S, whichheterocycle is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by one or more halogen,

[0033] R³⁴ is H, C₄₋₇ cycloalkyl (optionally substituted by one or moreC₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n), C₁₋₄alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH), or C₁₋₆ alkyl (optionallysubstituted by one or more halogen, C₄₋₇ cycloalkyl (optionallysubstituted by one or more C₁₋₄ alkyl), or phenyl (optionallysubstituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/orOH)),

[0034] R^(34a) is H, C₁₋₆ alkyl (optionally substituted by one or morehalogen, C₄₋₇ cycloalkyl (optionally substituted by one or more C₁₋₄alkyl), or phenyl (optionally substituted by (X)_(n), C₁₋₄ alkanoyloxy,NR³²R³³, CONR³²R³³ and/or OH)), C₄₋₇ cycloalkyl (optionally substitutedby one or more C₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n),C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH) or a naturally occuringamino acid substituent,

[0035] R³⁵ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl, phenyl (optionally substituted by one or more (X)_(n), C₁₋₄alkanoyl, NHR³², CON(R³²)₂, and/or OH), C₁₋₆ alkyl (optionallysubstituted by C₄₋₇ cycloalkyl optionally substituted by one or moreC₁₋₄ alkyl, or phenyl (optionally substituted by one or more (X)_(n),C₁₋₄ alkanoyl, NHR³², CON(R³²)₂, and/or OH)), C₁₋₄ alkoxy(C₁₋₄ alkyl),phenyl(C₁₋₄)alkyloxy(C₁₋₄)alkyl, tetrahydropyranyl, tetrahydrofuranyl,cinnamyl or trimethylsilyl,

[0036] R^(35a,b,c and d) are each independently H, C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, phenyl optionallysubstituted by one or more (X)_(n) or C₁₋₆ alkyl (optionally substitutedby C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄ alkyl, orphenyl optionally substituted by one or more (X)_(n)),

[0037] R³⁶ and R³⁷ each independently represent H, C₃₋₆ alkylalkenyl,C₄₋₇ cycloalkyl, phenyl optionally substituted by one or more (X)_(n),or C₁₋₆ alkyl (optionally substituted by C₄₋₇ cycloalkyl optionallysubstituted by one or more C₁₋₄ alkyl, or phenyl optionally substitutedby one or more (X)_(n)),

[0038] R³⁸ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl, phenyl optionally substituted by one or more (X)_(n), or C₁₋₆alkyl (optionally substituted by C₄₋₇ cycloalkyl optionally substitutedby one or more C₁₋₄ alkyl, or phenyl optionally substituted by one ormore (X)_(n)),

[0039] R² when taken alone is H or halogen;

[0040] or R¹ and R², when attached to adjacent carbon atoms, can betaken together with the carbon atoms to which they are attached, and mayrepresent Het^(1a);

[0041] Het^(1a) is a heterocyclic group containing up to 4 heteroatomsselected from N, O and S, which may comprise up to 3 rings (and ispreferably an optionally benzo-fused 5- to 7-membered heterocyclic ring)and which group is optionally substituted by one or more substituentsindependently selected from OH, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ hafoalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy,

[0042] which C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ haloalkoxygroups can be optionally substituted by one or more C₃₋₆ cycloalkyl,aryl(C₁₋₆)alkyl,

[0043] which aryl group is optionally substituted by one or morehalogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ haloalkoxy,

[0044] which latter C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄haloalkoxy groups can be optionally substituted by one or more NR²³R²⁴,NR S(O)_(n)R²⁴, NR²³C(O)_(m)R²⁴,

[0045] and if a S atom is present in a ring, it can be present as partof a —S—, S(O)— or —S(O₂)— group,

[0046] which R²³ and R²⁴ when taken alone independently represent H,C₁₋₄ alkyl, or C₁₋₄ haloalkyl,

[0047] or R²³ and R²⁴ can be taken together with the N atom to whichthey are attached, to form a 4- to 6-membered heterocyclic ringoptionally comprising one or more further heteroatoms selected from, N,O, or S, and which heterocyclic ring is optionally substituted by one ormore halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and/or C₁₋₄haloalkoxy groups,

[0048] R³ is H, CN, halogen, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₂₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle,NR¹²R¹³, CONR¹²R¹³, NY²WY¹, C₁₋₆ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,(each of which alkyl, alkenyl and alkynyl groups is optionallysubstituted by one or more CN, halogen, OH, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl, saturated heterocycle, NR¹²R¹³, CONR¹²R¹³and/or NY²WY¹),

[0049] R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl or C₃₋₁₀ alkynyl, each of whichgroups is linked to the N atom via a Sp³ carbon, and which group issubstituted by one or more substituents selected from:

[0050] C₂₋₆ alkoxy [substituted by one or more groups selected from OH,NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄ alkynyl, C₂₋₄ alkenyl,heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹), CO(aryl¹),CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹), CO₂CH₂(aryl¹),CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl¹),S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],

[0051] S(O)_(n)C₁₋₆ alkyl [optionally substituted by one or more groupsselected from OH, NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄alkynyl, C₂₋₄ alkenyl, heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹),CO(aryl¹), CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹),CO₂CH₂(aryl¹), CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl),S(O)_(n)(aryl¹), S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],

[0052] aryl²,

[0053] CO₂CH₂(heteroaryl¹),

[0054] CO₂CH₂(aryl¹),

[0055] cycloalkyl¹,

[0056] CO(heteroaryl¹),

[0057] CO(aryl¹),

[0058] OCO(aryl¹),

[0059] OCO(heteroaryl¹),

[0060] OCO(C₁₋₆ alkyl),

[0061] OCOCH₂CN,

[0062] CO₂(heteroaryl¹),

[0063] CO₂(aryl¹),

[0064] COCH₂(heteroaryl¹),

[0065] S(O)_(n)aryl¹,

[0066] S(O)_(n)CH₂aryl¹,

[0067] S(O)_(n)(heteroaryl¹),

[0068] S(O)_(n)CH₂(heteroaryl¹),

[0069] NHSO₂aryl¹,

[0070] NHSO₂(C₁₋₆ alkyl),

[0071] NHSO₂(heteroaryl¹),

[0072] NHSO₂CH₂(heteroaryl¹),

[0073] NHSO₂CH₂(aryl¹),

[0074] NHCOaryl¹,

[0075] NHCO(C₁₋₆ alkyl),

[0076] NHCONHaryl¹,

[0077] NHCONH(C₁₋₆ alkyl),

[0078] NHCOheteroaryl¹,

[0079] NHCONHheteroaryl¹,

[0080] NHCO₂(aryl¹),

[0081] NHCO₂(C₁₋₆ alkyl),

[0082] NHCO₂(heteroaryl¹),

[0083] ary²oxy,

[0084] heteroaryl¹oxy,

[0085] C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0086] C₂₋₆ alkanoyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0087] C₂₋₆ alkanoyloxy substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0088] cycloalkyl¹oxy,

[0089] COcycloalkyl¹,

[0090] heterocycle substituted by one or more substituent selected fromC₁₋₆ alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶,NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl),CO₂(C₁₋₆ alkyl), CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl,heterocyclyl, aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl,

[0091] heterocyclyloxy substituted by one or more substituent selectedfrom C₁₋₆ alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶,NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆alkyl), CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl,

[0092] WHEREIN aryl¹ is phenyl optionally fused to a C₅₋₇ carbocyclicring, which group is optionally substituted by one or more substituentselected from C₁₋₆ alkyl(optionally substituted by OH, CN or halogen),C₁₋₆ haloalkoxy, OH, ═O, NY²WY¹, halogen, C₁₋₆ alkoxy, CONR²⁵R²⁶,CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), COaryl,COheteroaryl, SO₂NR²⁵R²⁶, S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl),S(O)_(n)(heteroaryl), CO₂(C₁₋₆ alkyl), CO₂(aryl), CO₂(heteroaryl), CO₂H,(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), (CH₂)₁₋₄CO₂H, (CH₂)₁₋₄CO₂(aryl),(CH₂)₁₋₄CO₂(heteroaryl), O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), O(CH₂)₁₋₄CO₂H,O(CH₂)₁₋₄CO₂(aryl), O(CH₂)₁₋₄CO₂(heteroaryl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶ and C₃₋₇cycloalkyl,

[0093] aryl² is phenyl optionally fused to a C₅₋₇ carbocyclic ring,which group is substituted by one or more substituent selected from C₁₋₆alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶,CO(C₁₋₆ alkyl), COaryl, COheteroaryl, SO₂NR²⁵R²⁶, S(O)_(n)(C₁₋₆ alkyl),S(O)_(n)(aryl), S(O)_(n)(heteroaryl), CO₂(C₁₋₆ alkyl), CO₂(aryl),CO₂(heteroaryl), CO₂H, (CH₂)₁₋₄CO₂(C₁₋₆ alkyl), (CH₂)₁₋₄CO₂H,(CH₂)₁₋₄CO₂(aryl), (CH₂ ₁₋₄CO₂(heteroaryl), O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl),O(CH₂)₁₋₄CO₂H, O(CH₂)₁₋₄CO₂(aryl), O(CH₂)₁₋₄CO₂(heteroaryl), aryl,heterocyclyl, aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶and C₃₋₇ cycloalkyl,

[0094] heteroaryl¹ is heteroaryl optionally fused to a C₅₋₇ carbocyclicring, which group is optionally substituted by one or more substituentselected from C₁₋₆ alkyl(optionally substituted by OH, CN or halogen),C₁₋₆ haloalkoxy, OH, ═O, NY²WY¹, halogen, C₁₋₆ alkoxy, CONR²⁵R²⁶,CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), COaryl,COheteroaryl, SO₂NR²⁵R²⁶, S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl),S(O)_(n)(heteroaryl), CO₂(C₁₋₆ alkyl), CO₂(aryl), CO₂(heteroaryl), CO₂H,(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), (CH₂)₁₋₄CO₂H, (CH₂)₁₋₄CO₂(aryl),(CH₂)₁₋₄CO₂(heteroaryl), O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), O(CH₂)₁₋₄CO₂H,O(CH₂)₁₋₄CO₂(aryl), O(CH₂)₁₋₄CO₂(heteroaryl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶ and C₃₋₇cycloalkyl,

[0095] cycloalkyl¹ is a C₃₋₁₀ carbocyclic system with one or two ringsand which is substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy, CH₂(aryl¹),C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0096] WITH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS AHETERO-ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON

[0097] Z is a direct bond, CO or S(O)_(n) group,

[0098] B is (CH₂)_(p),

[0099] R¹² and R¹³ each independently represent H or C₁₋₄ alkyl,

[0100] or R¹² and R¹³ can be taken together with the N atom to whichthey are attached to form a 4- to 7-membered heterocycle optionallycomprising a further hetero moiety selected from NR¹⁶, O and/or S, andwhich is optionally substituted by one or more C₁₋₄ alkyl,

[0101] R¹⁴ and R¹⁵ each independently represent H, C₁₋₁₀ alkyl, C₃₋₁₀alkenyl, C₃₋₁₀ alkynyl, C₃₋₈ cycloalkyl, aryl or heteroaryl,

[0102] or R¹⁴ and R¹⁵ can be taken together with the N atom to whichthey are attached to form a 4- to 7-membered heterocycle optionallycomprising a further hetero moiety selected from NR¹⁶, O and/or S, andwhich is optionally substituted by one or more C₁₋₄ alkyl,

[0103] R¹⁶ is H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₁₋₆ alkylene)(C₃₋₈cycloalkyl) or (C₁₋₆ alkylene)aryl,

[0104] R⁵ and R⁸ when taken separately are each independently H, C₁₋₆alkyl,

[0105] R⁵ and R⁸ can be taken together with the carbon atoms to whichthey are joined to form a C₃₋₈ cycloalkyl ring,

[0106] R⁶, R⁷, R⁹ and R¹⁰ when taken separately are H,

[0107] R⁵ and R⁶ or R⁷ can be taken together with the carbon atoms towhich they are joined to form a C₃₋₈ cycloalkyl ring,

[0108] X is halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl or Cl₄haloalkoxy,

[0109] m is 1 or 2;

[0110] n is 0, 1 or 2;

[0111] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0112] q is 0 or 1;

[0113] “Naturally occuring amino acid substituent” means theα-substituent that occurs in any one of the following natural aminoacids, glycine, alanine, valine, leucine, isoleucine, phenylalanine,tryptophan, tyrosine, histidine, serine, threonine, methionine,cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine,arginine or proline;

[0114] “Heteroaryl” represents an aromatic ring containing up to fourheteroatoms independently selected from N, O and S, and if a S atom ispresent in the ring, it can be present as part of a —S—, S(O)— or—S(O)₂— group, and which may be joined to the remainder of the compoundvia any available atom(s);

[0115] “Heterocycle” is a group containing 1, 2 or 3 rings, and whichcontains up to 4 ring heteroatoms selected from N, O and S and up to 18ring carbon atoms;

[0116] “Aryl”, including in the definitions of “aryloxy”, etc., means agroup comprising a phenyl ring and which may incorporate a furthercarbocyclic ring fused to said phenyl ring and which may be joined tothe remainder of the compound via any available atom(s) (examples ofsuch groups include naphthyl, indanyl, etc.);

[0117] “Alkyl”, “alkenyl” and “alkynyl” groups can be linear or branchedif the number of carbon atoms allows;

[0118] “Cycloalkyl” groups can be polycyclic if the number of carbonatoms allows;

[0119] or a pharmaceutically or veterinarily acceptable derivative orprodrug thereof.

[0120] Where a fused heterocyclic group is present it can be attached tothe remainder of the compound via any available atom(s).

[0121] “Haloalkyl”, “haloalkoxy” groups and the like can contain morethan one halogen atom, and for instance can be per-halogenated.

[0122] Certain of the compounds of the invention can exist in one ormore geometric and/or stereoisomeric forms. The present inventionincludes all such individual isomers and salts and prodrugs thereof.

[0123] Certain compounds of the present invention may exist in more thanone tautomeric form. Similarly certain compounds of the invention mayhave zwitterionic forms. It is to be understood that the inventionembraces all such tautomers, zwitterions and their derivatives.

[0124] The pharmaceutically acceptable salts of the compounds of theformula (I) include the acid addition and the base salts thereof.Suitable acid addition salts are formed from acids which form non-toxicsalts and examples are the hydrochloride, hydrobromide, hydroiodide,sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate,acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate,succinate, benzoate, methanesulphonate, benzenesulphonate andp-toluenesulphonate salts. Suitable base salts are formed from baseswhich form non-toxic salts and examples are the aluminium, calcium,lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19(1977).

[0125] It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be transformed afteradministration into or onto the body, for example by metabolism, to formcompounds of formula (I) which are pharmacologically active. Suchderivatives are included in the term “prodrug”. It will further beappreciated by those skilled in the art that certain moieties known tothose skilled in the art as “pro-moieties”, for example as described in“Design of Prodrugs” by H Bundgaard (Elsevier) 1985, may be placed onappropriate functionalities when such functionalities are present incompounds of formula (I), also to form a “prodrug”. Further, certaincompounds of formula I may act as prodrugs of other compounds of formulaI. All protected derivatives, and prodrugs, of the compounds of formulaI are included within the scope of the invention.

[0126] Preferably the “Ar” ring represents phenyl or pyridyl.

[0127] Most preferably the “Ar” ring represents a group of formula:

[0128] Preferably R¹ when taken alone is OH, CN, halogen, NO₂, NH₂, NY²WY¹ or Het¹.

[0129] More preferably R¹ when taken alone is OH, CN, I, Cl, NH₂, NO₂,optionally benzo-fused heteroaryl, NHSO₂Y¹, NHCOY¹ or NHCO₂Y¹.

[0130] Yet more preferably R¹ when taken alone is OH, CN, I, Cl, NH₂,NO₂,1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl,thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO₂(C₁₋₆ alkyl),NHSO₂(C₁₋₆ alkyl substituted by methoxy, CONH₂, OH, CO₂(C₂₋₆ alkyl),phthalimido, NH₂ or halogen), NHSO₂NH₂, NHSO₂NH(C₁₋₆ alkyl), NHSO₂N(C₁₋₆alkyl)₂, NHSO₂Het_(1a), NHCO(C₁₋₆ alkyl) or NHCO₂(C₁₋₆ alkyl).

[0131] Even more preferably R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅,NHSO₂(n-C₃H₇), NHSO₂(i-C₃H₇), NHSO₂(n-C₄H₇), NHSO₂NH(i-C₃H₇),NHSO₂(N-methylimidazol-4-yl), NHSO₂(CH₂)₂OCH₃, NHSO₂(CH₂)₂OH,1,2,4-triazolyl or imidazol-2-yl.

[0132] Most preferably R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅ or imidazol-2-yl.

[0133] Preferably R² when taken alone is H.

[0134] R¹ and R² when taken together with the carbon atoms to which theyare attached are preferably an optionally benzo-fused 5- to 7-memberedheteroaryl ring optionally substituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.

[0135] More preferably R¹ and R² when taken together with the carbonatoms to which they are attached are a 5-membered heteroaryl moietyoptionally substituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.

[0136] Yet more preferably R¹ and R² when taken together with the carbonatoms to which they are attached are an imidazole group optionally2-substituted by CF₃.

[0137] Preferably X is Cl.

[0138] Preferably n is 0.

[0139] Preferably q is 0.

[0140] Preferably R³ is H, CN, C₁₋₆ alkyl (optionally substituted by oneor more halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl,C₂₋₆ alkanoyloxy, C₂₋₆ alkyloxycarbonyloxy, NR¹²R¹³, CONR¹²R¹³ and/orNY²WY¹).

[0141] More preferably R³ is H, CH₃, C₂H₅, i-C₃H₇, n-C₃H₇ or CH₂OCH₃.

[0142] Most preferably R³ is CH₃.

[0143] Preferably R⁴ is C₁₋₁₀ alkyl substituted by one or moresubstituents selected from:

[0144] C₂₋₆ alkoxy [substituted by one or more groups selected from OH,NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄ alkynyl, C₂₋₄ alkenyl,heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹), CO(aryl¹),CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹), CO₂CH₂(aryl¹),CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl¹),S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],

[0145] S(O)_(n)C₁₋₆ alkyl [optionally substituted by one or more groupsselected from OH, NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄alkynyl, C₂₋₄ alkenyl, heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹),CO(aryl¹), CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹),CO₂CH₂(aryl¹), CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl),S(O)_(n)(aryl¹), S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],

[0146] aryl²,

[0147] CO₂CH₂(heteroaryl¹),

[0148] CO₂CH₂(aryl¹),

[0149] cycloalkyl¹,

[0150] CO(heteroaryl¹),

[0151] CO(aryl¹),

[0152] OCO(aryl¹),

[0153] OCO(heteroaryl¹),

[0154] OCO(C₁₋₆ alkyl),

[0155] OCOCH₂CN,

[0156] CO₂(heteroaryl¹),

[0157] CO₂(aryl¹),

[0158] COCH₂(heteroaryl¹),

[0159] S(O)_(n)aryl¹,

[0160] S(O)_(n)CH₂aryl¹,

[0161] S(O)_(n)(heteroaryl¹),

[0162] S(O)_(n)CH₂(heteroaryl¹),

[0163] NHSO₂aryl¹,

[0164] NHSO₂(C₁₋₆ alkyl),

[0165] NHSO₂(heteroaryl¹),

[0166] NHSO₂CH₂(heteroaryl¹),

[0167] NHSO₂CH₂(aryl¹),

[0168] NHCOaryl¹,

[0169] NHCO(C₁₋₆ alkyl),

[0170] NHCONHaryl¹,

[0171] NHCONH(C₁₋₆ alkyl),

[0172] NHCOheteroaryl¹,

[0173] NHCONHheteroaryl¹,

[0174] NHCO₂(aryl¹),

[0175] NHCO₂(C₁₋₆ alkyl),

[0176] NHCO₂(heteroaryl¹),

[0177] aryl²oxy,

[0178] heteroaryl¹oxy,

[0179] C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0180] C₂₋₆ alkanoyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0181] C₂₋₆ alkanoyloxy substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,

[0182] cycloalkyl¹oxy,

[0183] COcycloalkyl¹,

[0184] heterocycle substituted by one or more substituent selected fromC₁₋₆ alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶,NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆alkyl), CH₂CO₂(C₁₋₆ alkyl), OCH₂CO(C₁₋₆ alkyl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl,

[0185] heterocyclyloxy substituted by one or more substituent selectedfrom C₁₋₆ alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶,NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆alkyl), CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl,

[0186] More preferably R⁴ is C₁₋₁₀ alkyl substituted by cycloalkyl¹.

[0187] Yet more preferably R⁴ is C₂₋₄ alkyl substituted by cycloalkyl¹.

[0188] Further more preferably R⁴ is propyl substituted by cycloalkyl¹.

[0189] Further yet more preferably R⁴ is propyl substituted by a C₃₋₁₀carbocyclic system with one or two rings and which is substituted by OH.

[0190] Even more preferably R⁴ is propyl substituted by (cyclohexylsubstituted by OH)

[0191] Most preferably R⁴ is (1-hydroxycyclohexyl)prop-3-yl.

[0192] Another preferred group of compounds are those wherein R⁴ takesthe values as specified in the Examples 145-203 below.

[0193] Preferably R⁵, R⁶, R⁷, R⁸ R⁹ and R¹⁰ are each taken separatelyand are H.

[0194] A preferred group of substances are those in which the “Ar” ring,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, q and (X)_(n) have the valuesas detailed in the Examples below.

[0195] The invention further provides synthetic methods for theproduction of compounds and salts of the invention, which are describedbelow and in the Examples and Preparations. The skilled man willappreciate that the compounds of the invention could be made by methodsother than those herein described, by adaptation of the methods hereindescribed and/or adaptation of methods known in the art, for example theart described herein, or using standard textbooks such as

[0196] “Comprehensive Organic Transformations—A Guide to FunctionalGroup Transformations”, RC Larock, VCH (1989 or later editions),

[0197] “Advanced Organic Chemistry—Reactions, Mechanisms and Structure”,J.March, Wiley-lnterscience (3rd or later editions),

[0198] “Organic Synthesis—The Disconnection Approach”, S Warren (Wiley),(1982 or later editions),

[0199] “Designing Organic Syntheses” S Warren (Wiley) (1983 or latereditions), “Guidebook To Organic Synthesis” R K Mackie and D M Smith(Longman) (1982 or later editions), etc.,and the references therein as aguide.

[0200] It is to be understood that the synthetic transformation methodsmentioned herein are exemplary only and they may be carried out invarious different sequences in order that the desired compounds can beefficiently assembled. The skilled chemist will exercise his judgementand skill as to the most efficient sequence of reactions for synthesisof a given target compound. For example, substituents may be added toand/or chemical transformations performed upon, different intermediatesto those mentioned hereinafter in conjunction with a particularreaction. This will depend inter alia on factors such as the nature ofother functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the synthesis. The procedures may beadapted as appropriate to the reactants, reagents and other reactionparameters in a manner that will be evident to the skilled person byreference to standard textbooks and to the examples providedhereinafter.

[0201] It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of the invention. This may be achieved byconventional methods, for example as described in “Protective Groups inOrganic Synthesis” by T W Greene and P G M Wuts, John Wiley & Sons Inc(1999), and refernces therein. Functional groups which may desirable toprotect include oxo, hydroxy, amino and carboxylic acid. Suitableprotecting groups for oxo include acetals, ketals (e.g. ethylene ketals)and dithianes. Suitable protecting groups for hydroxy includetrialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl.Suitable protecting groups for amino include tert-butyloxycarbonyl,9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protectinggroups for carboxylic acid include C₁₋₆ alkyl or benzyl esters.

[0202] In the Methods below, unless otherwise specified, thesubstituents are as defined above with reference to the compounds offormula (I).

[0203] The invention provides a process for the preparation of compoundsof formula I as defined above, or a pharmacutically or veterinarilyacceptable derivative thereof, which comprises:

[0204] (a) for compounds of formula I in which q is 0 and R¹ representsNY²WY¹, reacting a compound of formula II,

[0205]  with a compound of formula III,

Z¹-WY¹  III

[0206] wherein Z¹ is a suitable leaving group, such as halogen orY¹SO₂O—;

[0207] (b) for compounds of formula I in which q is 0 and R⁶ and R⁷ bothrepresent H, reduction of a compound of formula IV,

[0208]  using a suitable reducing agent;

[0209] (c) for compounds of formula I in which q is 0 and R⁹ and R¹⁰both represent H, reduction of a compound of formula V,

[0210]  using a suitable reducing agent;

[0211] (d) for compounds of formula I in which q is 0 and R¹ and R² areattached to adjacent carbon atoms and are taken together with the carbonatoms to which they are attached to represent Het^(1a), in whichHet^(1a) represents an imidazolo unit, reaction of a correspondingcompound of formula VI,

[0212]  with a compound of formula VII,

R^(y)CO₂H  VII

[0213] wherein R^(y) represents H or any of the optional substituents onHet^(1a) (as defined above), preferably H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

[0214] (e) where q is 0, reacting a compound of formula VIII,

[0215]  with a compound of formula IX,

R⁴-Lg  IX

[0216] wherein Lg is a leaving group;

[0217] (f) for compounds of formula I in which q is 0 and R⁶, R⁷, R⁹ andR¹⁰ are all H, reduction of a compound of formula X,

[0218]  with a suitable reducing agent;

[0219] (g) for compounds of formula I in which q is 0 and R¹ representsOH, reacting a compound of formula II in which Y² is H, as definedabove, with fluoroboric acid and isoamyl nitrite;

[0220] (h) for compounds of formula I in which q is 0 and R¹ representsCl, reacting a compound of formula II in which Y² is H, as definedabove, with sodium nitrite in the presence of dilute acid, followed byreaction with copper (I) chloride in the presence of concentrated acid;

[0221] (i) for compounds of formula I in which q is 1, reacting acompound of formula I where q is 0 with a suitable oxidising agent suchas aqueous hydrogen peroxide;

[0222] j) for compounds of formula I where q is 0, by reduction of acorresponding compound of formula XXXI,

[0223] where R^(4a)CH₂ takes the same meaning as R⁴ as defined above; or

[0224] (k) for compounds of formula (I) where q is 0, reductiveamination reaction of the amine of formula VIII above with an aldehydeof formula R^(4a)-CHO wherein R^(4a)CH₂ takes the same meaning as R⁴ asdefined above,

[0225] and where desired or necessary converting the resulting compoundof formula I into a pharmaceutically or veterinarily acceptablederivative or vice versa.

[0226] In process (a), the reaction may be carried out at between 0° C.and room temperature in the presence of a suitable base (e.g. pyridine)and an appropriate organic solvent (e.g. dichloromethane).

[0227] Compounds of formula II may be prepared by reduction of acorresponding compound of formula XI or formula XII,

[0228] in the presence of a suitable reducing agent, such as lithiumaluminium hydride. The reaction may be carried out at between roomtemperature and reflux temperature in the presence of a suitable solvent(e.g. tetrahydrofuran).

[0229] Compounds of formula XI and XII may be prepared by reduction ofthe corresponding —NO₂ compounds under conditions that are well known tothose skilled in the art (e.g. using H₂/Raney Ni or in the presence ofCaCl₂ and iron powder, in the presence of a suitable solvent system(e.g. EtOH, EtOAc and/or water)). The skilled person will appreciatethat, in preparing a compound of formula II, in which Y² is H, from sucha corresponding —NO₂ compound, the two above-mentioned reduction stepsmay be performed in the same step or sequentially in any order.

[0230] The said corresponding —NO₂ compounds may be prepared by reactionof a compound of formula XII or formula XIV, as appropriate,

[0231] wherein L¹ represents a suitable leaving group [such as halo(e.g. chloro or bromo)], L² represents a suitable leaving group (such asC₁₋₃ alkoxy) and R³ is as defined above, with a compound of formula XV,

R⁴NH₂  XV

[0232] The reaction may be carried out at between room temperature andreflux temperature in the presence of a suitable base (e.g. NaHCO₃) andan appropriate organic solvent (e.g. dimethylformamide), or at a highertemperature (e.g. between 50 and 200° C., preferably between 100 and160° C.) in the presence of neat compound of formula XV.

[0233] Compounds of formula XIII and XIV may be prepared in accordancewith standard techniques. For example, compounds of formula XIII and XIVmay be prepared by reacting a corresponding compound of formula XVI orXVII,

[0234] with a compound of formula XVIII or XIX respectively,

N₂CHR⁵COL²  XVIII

N₂CHR⁸COL²  XIX

[0235] wherein L² is as defined above. The reaction may be carried outat room temperature in the presence of a suitable catalyst [e.g.Rh₂(OAc)₄] and an appropriate non-protic organic solvent (e.g.dichloromethane).

[0236] Compounds of formula XVI and formula XVII are available or can beprepared using known techniques. Compounds of formula XVI and formulaXVII may, for example, be prepared from corresponding compounds offormula XX,

[0237] for example by performing a Wittig reaction using an appropriateprovider of the nucleophilic group RO₂C—CR⁵H⁻ or RO₂C—CR⁸H⁻ (wherein Rrepresents lower (e.g. C₁₋₃) alkyl), as appropriate, under conditionsthat are well known to those skilled in the art. The —CO₂R group of theresulting compound may be converted to an appropriate —CH₂L¹ group usingstandard techniques (e.g. reduction of the ester to the primary alcoholand conversion of the latter to an alkyl halide) under conditions thatare well known to those skilled in the art.

[0238] In processes (b) and (c), suitable reducing agents includelithium aluminium hydride. The reaction may be carried out at betweenroom temperature and reflux temperature in the presence of a suitablesolvent (e.g. tetrahydrofuran).

[0239] Compounds of formula II may be prepared by reduction of thecorresponding compound of formula XXX,

[0240] by analogy to the process steps mentioned above.

[0241] Compounds of formula IV and V may be prepared respectively fromcompounds of formula XXI and XXII,

[0242] wherein L³ represents a group that is capable of undergoingfunctional group transformations (e.g. cyano) using standard functionalgroup substitution or conversion techniques.

[0243] For example:

[0244] (1) Compounds of formula IV and V in which R¹ represents1,2,4-triazol-3-yl may be prepared by reaction of an appropriatecompound of formula XXI or XXII in which L³ represents —CN with HCl(gas) in the presence of an appropriate lower alkyl alcohol (e.g.ethanol), for example at between 0° C. and room temperature, followed byreaction of the resultant intermediate with formic acid hydrazide (e.g.at reflux temperature, with or without the presence of a suitableorganic solvent (e.g. methanol), followed by, if necessary, removing thesolvent and heating the resultant residue to a high temperature (e.g.about 150° C.)).

[0245] (2) Compounds of formula IV and V in which R¹ representsimidazol-2-yl may be prepared by reaction of an appropriate compound offormula XXI or XXII in which L³ represents —CN with HCl (gas) in thepresence of an appropriate lower alkyl alcohol (e.g. ethanol), forexample at between 0° C. and room temperature, followed by reaction ofthe resultant intermediate with aminoacetaldehyde dialkylacetal (e.g.dimethylacetal) (e.g. at or around reflux temperature in the presence ofan appropriate solvent, such as methanol).

[0246] (3) Compounds of formula IV and V in which R¹ represents1,2,3-triazol-5-yl may be prepared by reaction of an appropriatecompound of formula XXI or XXII in which L ³ represents —CN withdiazomethane, or a protected (e.g. trialkylsilyl) derivative thereof,for example at between 0° C. and room temperature in the presence of asuitable base (e.g. n-BuLi) and, optionally, an appropriate organicsolvent (e.g. THF), followed by removal of the protecting group asnecessary.

[0247] (4) Compounds of formula IV and V in which R¹ representsbenzimidazol-2-yl may be prepared by reaction of an appropriate compoundof formula XXI or XXII in which L³ represents C═NH(OEt) with1,2-diaminobenzene. The reaction may be carried out in a solvent such asmethanol, at an elevated temperature (such as the reflux temperature ofthe solvent). Preparations 81, etc. provide further details.

[0248] Compounds of formula IV and V in which R¹ represents Het¹ mayalso be prepared from compounds of formula XI and XII respectivelyaccording to the following scheme:

[0249] wherein Het¹ is defined above. Further details may be found inPreparations 67, 68, etc. in WO00/39089, herein incorporated byreference in its entirety.

[0250] Compounds of formula XXI and XXII may be prepared in analogousfashion to methods described herein, for example those describedhereinbefore for preparation of compounds of formula II.

[0251] Other compounds of formula (IV) and (V) may be prepared byanalogy with methods described herein (e.g. by analogy with methodsdescribed hereinbefore for preparation of compounds of formula XI andXII (and especially the corresponding —NO₂ compound)).

[0252] In process (d), the reaction may be carried out by heating underreflux, with or without the presence of an appropriate organic solvent.

[0253] Compounds of formula VI may be prepared using known techniques.For example, compounds of formula VI may be prepared by nitration (atthe 4-position) of a corresponding 3-aminobenzene compound (a compoundof formula II), which latter compound may be activated by converting the3-amino group to a 3-amido group, followed by hydrolysis of the amideand reduction of the 4-nitrobenzene compound. All of these reactions maybe performed using techniques that are familiar to the skilled person,and are illustrated in Preparations 45-48, etc. below.

[0254] In process (e), suitable leaving groups that Lg may representinclude halogen, such as bromine, or a sulphonate group such astosylate, mesylate or triflate. The reaction may be carried out in apolar solvent that does not adversely affect the reaction, at a suitabletemperature, e.g. 0-150° C., in the presence of a base. A catalyst suchas sodium iodide may optionally be added.

[0255] Preferable choices are a slight excess of R⁴-Lg, where Lg=Cl orBr, an excess of base (2.0-4.0 eq), such as K₂CO₃, NaHCO₃, or a tertiaryamine, such as triethylamine or Hunigs base, in a polar solvent, such asTHF, DMF, or MeCN, at between 40 and 120° C., optionally in the presenceof a catalyst such as Nal or Kl, for 2-24 hr.

[0256] see R C Larrock in “Comprehensive Organic Transformations-A Guideto Functional Group Preparations”, VCH, (1989), p 397, and referencescited therein.

[0257] Compounds of formula VIII may be prepared from compounds offormula XXV,

[0258] wherein Pg represents a suitable protecting group. Suitableprotecting groups include allyl, which may be removed using a palladium(0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc.below). Compounds of formula XXV may be prepared using analogous methodsto those described herein for the preparation of compounds of formula I.

[0259] In process (f), suitable reducing agents include lithiumaluminium hydride. The reaction may be carried out in a solvent thatdoes not adversely affect the reaction (for example tetrahydrofuran), atan elevated temperature (for example the reflux temperature of thesolvent).

[0260] Compounds of formula X may be prepared by reacting a compound offormula XXVI with a compound of formula XXVII in the presence of anoxidizing agent. Suitable oxidizing agents include manganese dioxide.The reaction may be carried out in a solvent that does not adverselyaffect the reaction (for example dioxan), at an elevated temperaturesuch as the reflux temperature of the solvent (for example seePreparation 77, WO00/39089). The intermediate compounds XXIXa areisolatable using suitable conditions (e.g. see Preparation 58,WO00/39089).

[0261] Compounds of formula XXVI may be prepared from compounds offormula XXVIII, by reaction of the corresponding ketone with hydrazinemonohydrate using known techniques (and as described in Preparation 76,etc. WO00/39089).

[0262] Process (f) is particularly useful when Ar represents anoptionally benzo-fused 5- or 6-membered heteroaryl ring. A similarmethodology may be used to obtain compounds of formula II: the precursornitro compound may be prepared from a compound of formula XX, as definedabove, using the steps described above (see for example Preparations57-61, WO00/39089).

[0263] In process (g), the reaction may be carried out in a solvent thatdoes not adversely affect the reaction (for example ethanol), firstbelow room temperature and then at an elevated temperature (Examples 79,etc. WO00/39089, provides further details).

[0264] In process (h), suitable acids include dilute aqueoushydrochloric acid and concentrated hydrochloric acid, respectively. Thereaction may be carried out at or around room temperature, finishing atan elevated temperature (for example 90° C.). Example 51 WO00/39089provides further details.

[0265] In process (j), the compound of formula XXXI may be prepared byacylation of the compound of formula VIII as defined above, with anacylating agent of the formula R^(4a)CO-L_(g), where L_(g) is a suitableleaving group as defined above with respect to (e), and includeshalogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR^(4a) (i.e. an acidanhydride) and the like, well known to those practising in the art. Seefor example the conditions used for Preparation 47. The coupling canoptionally be carried out in the presence of a catalyst, for exampleDMAP, in a suitable solvent; see R C Larrock in “Comprehensive OrganicTransformations-A Guide to Functional Group Preparations”, secondedition, (1999), pp 1941-1949, and references cited therein. Preferablythe carboxylic acid (0.9-1.1 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HCl (1-1.5 eq) and1-hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15min and then the amine salt (1 eq) and base (NaHCO3 or organic base,Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr atRT.

[0266] The amide bond can be reduced with a suitable reducing agent, forexample lithium aluminium hydride or borane, in an ethereal solvent,such as THF, at 0-100° C. to generate the desired tertiary amine, see RC Larrock in “Comprehensive Organic Transformations-A Guide toFunctional Group Preparations”, VCH, (1989), pp 432-434, and referencescited therein. Preferably the amide (1.0 eq) is treated with lithiumaluminium hydride (1.0-3 eq), at 0° C.-RT, in THF, for 1-24 hr.

[0267] In process (k) the appropriate aldehyde is reacted with an amine,optionally present as an acid addition salt, in the presence of asuitable reducing agent (such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Nicatalysts). The reaction is suitably performed in the presence of aceticacid at 0-100° C. in THF, methanol, DCM (dichloromethane), or DCE(1,2-dichloroethane), for a suitable time such as 1-24 hr. Preferablythe amine salt, such as the trifluoroacetic acid (TFA) salt, is treatedwith an organic base (1-3 mole equivalents), such as triethylamine orHunigs base, and then the aldehyde (1-1.5 mole equivalents), followed bysodium triacetoxyborohydride (1-2.0 mole equivalents), in DCM or DCE, atroom temperature for 2-24 hr. see R C Larrock; “Comprehensive OrganicTransformations-A Guide to Functional Group Preparations”, secondedition, (1999), p 835-842, and references cited therein, andAbdel-Magid et al, J. Org. Chem., 1996, 61, 3849.

[0268] The aldehydes used in this process may be prepared from thecorresponding alcohols using suitable oxidising agents; see R C Larrockin “Comprehensive Organic Transformations-A Guide to Functional GroupPreparations”, second edition, (1999), pp 1234-1236 and 1238-1247, andreferences cited therein. Preferred oxidants are tetrapropylammoniumperruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidationand related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), andDess-Martin Periodinane reagent (Dess et al., J. Org. Chem., 1983, 48,4155-4156).

[0269] Various functional group interconversions on compounds of formula(I), or intermediates thereto, may be carried out to give differentcompounds of formula (I) or intermediates. Some of these are mentionedbelow.

[0270] Anilines can be converted to a urea using potassium cyanate(excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem.,1985, 28, 1427-1432.

[0271] Esters can be converted to the corresponding alcohols using asuitable reducing agent, see Larock, Comprehensive OrganicTransformations-A Guide to Functional Group Preparations, secondedition, (1999), pp 1117-1120 and references cited therein. Suitablereducing agents include diisobutylaluminium hydride (DIBAL, seeWinterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride(LiAIH4, see Brown, Org. Reactions, 1951, 6, 469) - viz. reaction of thetype:

[0272] Alcohols can be prepared from a corresponding acid using asuitable reducing agent; see Larock, Comprehensive OrganicTransformations-A Guide to Functional Group Preparations, secondedition, (1999), pp 1114-1116. Preferably the reducing agent is eitherborane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4eq), in an ethereal solvent, such as THF, 0-80° C., for 1-24 hr. - viz.reaction of the type:

[0273] Direct methods to prepare alkyl halides and alyl sulphonates fromtheir alcohols are described by R C Larrock, Comprehensive OrganicTransformations-A Guide to Functional Group Preparations, secondedition, (1999),

[0274] pp 689-700, and references cited therein.

[0275] Benzylacetals can be treated with a suitable reducing agent inthe presence of a Lewis acid or organic acid to give benyloxyalcohols.

[0276] For representative examples see Organic Preparations andProcedures, Int., 1991, 23, 4, 427-431, ZrCl4/LiAIH4; J. Org. Chem.,1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic Preparations andProcedures, Int., 1985, 17(1), 11-16, NaBH4/TFA.

[0277] viz. reaction of the type:

[0278] It will be apparent to those skilled in the art that compounds offormula I may be converted to other compounds of formula I using knowntechniques. For example, compounds of formula I in which Y¹ representsalkoxycarbonyl may be converted to compounds in which Y¹ representsalkyl substituted by OH, by reduction using LiAIH₄ (Example 57 providesfurther details). Similarly, intermediate compounds may beinterconverted using known techniques (see for example Preparation 85).

[0279] The intermediate compounds such as those of formulae III, XV,XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivativesthereof, when not commercially available or not subsequently described,may be obtained either by analogy with the processes described herein,or by conventional synthetic procedures, in accordance with standardtechniques, from readily available starting materials using appropriatereagents and reaction conditions.

[0280] The invention further provides the intermediate compounds offormulae II, IV, V, VI, X, X^(a), XI, XI, XXI, XXII, XXIII, XXIV, XXIX,XXIXa, XXX, and XXXI as defined above.

[0281] Where desired or necessary, the compound of formula (I) can beconverted into a pharmaceutically acceptable salt thereof, convenientlyby mixing together solutions of a compound of formula (I) and thedesired acid or base, as appropriate. The salt may be precipitated fromsolution and collected by filtration, or may be collected by other meanssuch as by evaporation of the solvent. Both types of salt may also beformed or interconverted using ion-exchange resin techniques.

[0282] The compounds of the invention may be purified by conventionalmethods, for example separation of diastereomers may be achieved byconventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. of a stereoisomeric mixture of a compound offormula (I) or a salt thereof. An individual enantiomer of a compound offormula (I) may also be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereomeric salts formed by reaction of thecorresponding racemate with a suitably optically active base or acid.

[0283] The compounds of the invention are useful because they possesspharmacological activity in animals, especially mammals includinghumans. They are therefore indicated as pharmaceuticals and, inparticular, for use as animal medicaments.

[0284] According to a further aspect of the invention there is providedthe compounds of the invention for use as medicaments, such aspharmaceuticals and animal medicaments, such as for the treatment ofopiate-mediated diseases and conditions.

[0285] By the term “treatment”, this term includes both therapeutic(curative) and prophylactic treatment.

[0286] In particular, the substances of the invention have been found tobe useful in the treatment of diseases and conditions modulated viaopiate receptors, such as irritable bowel syndrome; constipation;nausea; vomiting; pruritus; eating disorders; opiate overdoses;depression; smoking and alcohol addiction; sexual dysfunction; shock;stroke; spinal damage and/or head trauma; and conditions characterisedby having pruritis as a symptom.

[0287] Thus, according to a further aspect of the invention there isprovided the use of the compounds of the invention in the manufacture ofa medicament for the treatment of a disease modulated via an opiatereceptor. There is further provided the use of the compounds of theinvention in the manufacture of a medicament for the treatment of asirritable bowel syndrome; constipation; nausea; vomiting; pruritus;eating disorders; opiate overdoses; depression; smoking and alcoholaddiction; sexual dysfunction; shock; stroke; spinal damage and/or headtrauma; and conditions characterised by having pruritis as a symptom.

[0288] The compounds of the invention are thus expected to be useful forthe curative or prophylactic treatment of pruritic dermatoses includingallergic dermatitis and atopy in animals and humans. Other diseases andconditions which may be mentioned include contact dermatitis, psoriasis,eczema and insect bites.

[0289] Thus, the invention provides a method of treating or preventing adisease modulated via an opiate receptor. There is further provided amethod of treating irritable bowel syndrome; constipation; nausea;vomiting; pruritus; eating disorders; opiate overdoses; depression;smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinaldamage and/or head trauma; or a medical condition characterised bypruritus as a symptom in an animal (e.g. a mammal), which comprisesadministering a therapeutically effective amount of a compound of theinvention to an animal in need of such treatment.

[0290] The compounds of the invention will normally be administeredorally or by any parenteral route, in the form of pharmaceuticalpreparations comprising the active ingredient, optionally in the form ofa non-toxic organic, or inorganic, acid, or base, addition salt, in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated, as well as the route of administration, thecompositions may be administered at varying doses (see below).

[0291] While it is possible to administer a compound of the inventiondirectly without any formulation, the compounds are preferably employedin the form of a pharmaceutical, or veterinary, formulation comprising apharmaceutically, or veterinarily, acceptable carrier, diluent orexcipient and a compound of the invention. The carrier, diluent orexcipient may be selected with due regard to the intended route ofadministration and standard pharmaceutical, and/or veterinary, practice.Pharmaceutical compositions comprising the compounds of the inventionmay contain from 0.1 percent by weight to 90.0 percent by weight of theactive ingredient.

[0292] The methods by which the compounds may be administered forveterinary use include oral administration by capsule, bolus, tablet ordrench, topical administration as an ointment, a pour-on, spot-on, dip,spray, mousse, shampoo, collar or powder formulation or, alternatively,they can be administered by injection (eg subcutaneously,intramuscularly or intravenously), or as an implant. Such formulationsmay be prepared in a conventional manner in accordance with standardveterinary practice.

[0293] The formulations will vary with regard to the weight of activecompound contained therein, depending on the species of animal to betreated, the severity and type of infection and the body weight of theanimal. For parenteral, topical and oral administration, typical doseranges of the active ingredient are 0.01 to 100 mg per kg of body weightof the animal. Preferably the range is 0.1 to 10 mg per kg.

[0294] In any event, the veterinary practitioner, or the skilled person,will be able to determine the actual dosage which will be most suitablefor an individual patient, which may vary with the species, age, weightand response of the particular patient. The above dosages are exemplaryof the average case; there can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention.

[0295] For veterinary use, the compounds of the invention are ofparticular value for treating pruritus in domestic animals such as catsand dogs and in horses.

[0296] As an alternative for treating animals, the compounds may beadministered with the animal feedstuff and for this purpose aconcentrated feed additive or premix may be prepared for mixing with thenormal animal feed.

[0297] For human use, the compounds are administered as a pharmaceuticalformulation containing the active ingredient together with apharmaceutically acceptable diluent or carrier. Such compositionsinclude conventional tablet, capsule and ointment preparations which areformulated in accordance with standard pharmaceutical practice.

[0298] Compounds of the invention may be administered either alone or incombination with one or more agents used in the treatment or prophylaxisof disease or in the reduction or suppression of symptoms. Examples ofsuch agents (which are provided by way of illustration and should not beconstrued as limiting) include antiparasitics, eg fipronil, lufenuron,imidacloprid, avermectins (eg abamectin, ivermectin, doramectin),milbemycins, organophosphates, pyrethroids; antihistamines, egchlorpheniramine, trimeprazine, diphenhydramine, doxylamine;antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin,amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin,ampicillin, amoxycillin; anti-inflammatories eg prednisolone,betamethasone, dexamethasone, carprofen, ketoprofen; dietarysupplements, eg gamma-linoleic acid; and emollients. Therefore, theinvention further provides a product containing a compound of theinvention and one or more selected compounds from the above list as acombined preparation for simultaneous, separate or sequential use in thetreatment of diseases modulated via opiate receptors

[0299] The skilled person will also appreciate that compounds of theinvention may be taken as a single dose or on an “as required” basis(i.e. as needed or desired).

[0300] Thus, according to a further aspect of the invention there isprovided a pharmaceutical, or veterinary, formulation including acompound of the invention in admixture with a pharmaceutically, orveterinarily, acceptable adjuvant, diluent or carrier.

[0301] Compounds of the invention may also have the advantage that, inthe treatment of human and/or animal patients, they may be moreefficacious than, be less toxic than, have a broader range of activitythan, be more potent than, produce fewer side effects than, be moreeasily absorbed than, or they may have other useful pharmacologicalproperties over, compounds known in the prior art.

[0302] The biological activities of the compounds of the presentinvention were determined by the following test method.

[0303] Biological Test

[0304] Compounds of the present invention have been found to displayactivity in three opioid receptor binding assays selective for the mu,kappa and delta opioid receptors in dog brain. The assays were conductedby the following procedure.

[0305] Laboratory bred beagles were used as a source of dog braintissue. Animals were euthanaised, their brains removed and thecerebellum discarded. The remaining brain tissue was sectioned intosmall pieces approximately 3 g in weight and homogenised in 50 mM TrispH 7.4 buffer at 4° C. using a Kinematica Polytron tissue homogeniser.The resulting homogenate was centrifuged at 48,400×g for 10 minutes andthe supernatant discarded. The pellet was resuspended in Tris buffer andincubated at 37° C. for 10 minutes. Centrifugation, resuspension andincubation steps were repeated twice more, and the final pellet wasresuspended in Tris buffer and stored at −80° C. Membrane materialprepared in this manner could be stored for up to four weeks prior touse.

[0306] For mu, kappa and delta assays, increasing concentrations ofexperimental compound (5×10⁻¹² to 10⁻⁵M), Tris buffer and ³H ligand,(mu=[D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-Enkephalin, DAMGO; kappa=U-69,593;delta=Enkephalin, [D-pen^(2,5)] DPDPE), were combined in polystyrenetubes. The reaction was initiated by the addition of tissue, and themixture was incubated at room temperature for 90 minutes. The reactionwas terminated by rapid filtration using a Brandel Cell Harvester™through Betaplate™ GF/A glass fibre filters pre-soaked in 50 mM Tris pH7.4, 0.1% polyethylenimine buffer. The filters were then washed threetimes with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays,washed filters were placed in bags and Starscint™ scintillant added, forthe kappa assay Meltilex™ B/HS solid scintillant was used. Bagscontaining the filters and scintillant were heat sealed and counted by aBetaplate™ 1204 beta counter.

[0307] Duplicate samples were run for each experimental compound and thedata generated was analysed using IC₅₀ analysis software in GraphpadPrism. Ki values were calculated using Graphpad Prism according to thefollowing formula:

Ki=IC₅₀/1+[³H ligand] /K_(D)

[0308] where IC₅₀ is the concentration at which 50% of the ³H ligand isdisplaced by the test compound and K_(D) is the dissociation constantfor the ³H ligand at the receptor site.

[0309] Biological Activity

[0310] The Ki values of certain compounds of the present invention inthe opioid receptor binding assays were determined, and were found tohave Ki values of 4000 nM or less for the μ receptor.

[0311] It is believed that the methods used in the following Examplesproduce compounds having the relative stereochemistry shown below, andsuch compounds are preferred:

[0312] wherein R¹⁻⁴ and (X)_(n) are as defined above.

[0313] The invention is illustrated by the following Examples andPreparations in which the following abbreviations may be used:

[0314] APCI=atmospheric pressure chemical ionization

[0315] DMF=dimethylformamide

[0316] DMSO=dimethylsulphoxide

[0317] d (in relation to time)=day

[0318] d (in relation to NMR)=doublet

[0319] ES (in relation to MS)=electrospray

[0320] EtOAc=ethyl acetate

[0321] EtOH=ethanol

[0322] h=hour

[0323] MeOH=methanol

[0324] min=minute

[0325] MS=mass spectrum

[0326] n-BuOH=n-butanol

[0327] ODS=octadecylsilyl

[0328] THF=tetrahydrofuran

[0329] TSP=thermospray

[0330] Melting points were determined using a Gallenkamp melting pointapparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectraldata relate to ¹H and were obtained using a Varian Unity 300 or 400spectrometer, the observed chemical shifts (δ) being consistent with theproposed structures. Mass spectral (MS) data were obtained on a FisonsInstruments Trio 1000, or a Fisons Instruments Trio 1000 APCI, or aFinnigan Navigator MS, or a Micromass Platform LC spectrometer. Thecalculated and observed ions quoted refer to the isotopic composition oflowest mass. Room temperature means 20 to 25° C. The mass spectrometerwhich is used as a detector on the analytical HPLC-MS system is aMicromass VG Platform II, running on Masslynx/Openlynx software. Thesystem can run positive and negative ion with either Electrospray orAPCI probes and is calibrated to 1972 Daltons, it collects full Diodearray data from 190 nm to 600 nm.

[0331] HPLC means high performance liquid chromatography. HPLCconditions used were:

[0332] Condition 1: Rainin Dynamax™ column, 8μ ODS, 24×300 mm, columntemperature 40° C., flow rate 45 ml/min, eluting with methanol:water(70:30), UV detection of product at 246 nm.

[0333] Condition 2: Rainin Dynamax™ column, 5μ ODS, 21.6×250 mm, columntemperature 40° C., flow rate 5 ml/min, eluting with acetonitrile:water(50:50), UV detection of product at 246 nm.

[0334] Condition 3: Rainin Dynamax™ column, 8μ ODS, 41×250 mm, columntemperature 40° C., flow rate 45 ml/min, eluting with acetonitrile:0.1Maqueous ammonium acetate buffer (50:50), UV detection of product at 235nm.

[0335] Condition 4: Phenomenex Magellan™ column, 5μ C₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.1 M aqueous ammonium acetate buffer (30:70 to95:5 over 10 min), UV detection of product at 220 nm.

[0336] Condition 5: Phenomenex Magellan™ column, 51μ ODS, 21.2×150 mm,column temperature 40° C., flow rate 20 ml/min, eluting with a gradientof acetonitrile:0.1 M aqueous ammonium acetate buffer (5:95 to 95:5 over20 min), UV detection of product at 215 nm.

[0337] Condition 6: Phenomenex Magellan™ column, 5μ C₁₈ silica, 4.6×150mm, column temperature 40° C., flow rate 1 ml/min, eluting with agradient of acetonitrile:0.1M aqueous heptanesulphonic acid (10:90 to90:10 over 30 min), UV detection of product at 220 nm.

[0338] Condition 7: Phenomenex Magellan™ column, 5μ C₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.05M aqueous ammonium acetate buffer (50:50for 15 min then 50:50 to 90:10 over 5 min), UV detection of product at220 nm.

[0339] Condition 8: Phenomenex Magellen™ column, 5μ C₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.1M aqueous ammonium acetate buffer (15:85 to85:15), UV detection of product at 220 nm.

[0340] Condition 9: Phenomenex Magellen™ column, 5μ ODS, 10×150 mm,column temperature 40° C., flow rate 5 ml/min, eluting with a gradientof acetonitrile:0.1M aqueous ammonium acetate buffer (5:95 to 30:70 over5 min then 30:70 for a further 20 min), UV detection of product at 225nm.

[0341] Condition 10: Phenomenex Magellan™ column, 5μ C₁₈ silica,21.2×150 mm, column temperature 40° C., flow rate 20 ml/min, elutingwith a gradient of acetonitrile:0.1M aqueous ammonium acetate (5:95 to40:60 over 5 min then 40:60 for a further 25 min), UV detection ofproduct at 210 nm.

[0342] Condition 11: Phenomenex Magellan™ column, 5μ ODS, 10×150 mm,column temperature 40° C., flow rate 5 ml/min, eluting with a gradientof acetonitrile : water (5:95 to 55:45 over 5 min), UV detection ofproduct at 210 nm.

[0343] The free base form of the azabicycles could be obtained from thehydrochloride or acetate salts, for example, in the following way. Thesalt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate solution (20 ml). The basicmixture was separated and the aqueous layer was extracted withdichloromethane (2×20 ml). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo to give the free base.

[0344] SPE cartridge refers to a solid phase extraction cartridge. Thesecan be commercially obtained from Varian (Mega Bond Elut®) or Isolute™.NB “Examples” numbered 1-144 are compounds related to the instantinvention, but with different R⁴ groups, and are disclosed as such inInternational Patent Application no. WO00/39089, herein incorporated byreference in its entirety.

[0345] A number of further Examples, such as those in the table below,can be made via the processes A-K outlined below and in the experimentaldetails following the table

[0346] Process A

[0347] Alkylation

[0348] Alkylation of the amine of formula VIII or a salt thereof withR⁴Lg, where Lg is a suitable leaving group, such as a halogen, triflate,mesylate, etc., in the presence of a base, optionally in the presence ofa catalyst, in a polar solvent, at between 0 and 150° C.

[0349] Preferably the alkylation is carried out with R⁴Lg (slightexcess), where Lg=Cl or Br, an excess of base (2.0-4.0 eq), such asK₂CO₃, NaHCO₃, or a tertiary amine, such as triethylamine or Hunigsbase, in a polar solvent, such as THF, DMF, or MeCN, at between 40 and120° C., optionally in the presence of a catalyst such as NaI or KI, for2-24 hr.

[0350] See R C Larrock in “Comprehensive Organic Transformations-A Guideto Functional Group Preparations”, VCH, (1989), p 397, and referencescited therein.

[0351] For Example:

[0352] Conditions: Amine salt (1.0 eq), RX (1.1 eq), NaHCO3 (2-4.0 eq),DMF, Nal (cat), 40-120° C.

[0353] Process B

[0354] Reductive Amination

[0355] Treating an appropriate aldehyde R^(4a)CHO with an amine offormula VIII in the presence of a suitable reducing agent (such assodium cyanoborohydride, sodium triacetoxyborohydride, or catalytichydrogenation with Pd, Pt or Ni catalysts). The reaction is oftenperformed in the presence of acetic acid at 0-100° C. in THF, MeOH, DCM,or DCE (1,2-dichloroethane), for 1-24 hr.

[0356] Preferably the amine salt is treated with an organic base (1-3eq), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5eq), followed by sodium triacetoxyborohydride (1-2.0 eq), indichloromethane or DCE, at room temperature for 2-24 hr. See R CLarrock; “Comprehensive Organic Transformations-A Guide to FunctionalGroup Preparations”, second edition, (1999), p 835-842, and referencescited therein, and Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849.

[0357] For example:

[0358] Conditions: Amine salt (1.0 eq), RCHO (1-1.5 eq), Et3N (1-3 eq),Na(OAc)3BH (1-2 eq), DCM RT.

[0359] Process C

[0360] Reduction of Amide or Formula XXXI

[0361] The amide carbonyl can be reduced with a suitable reducing agent,for example lithium aluminium hydride or borane, in an ethereal solvent,such as THF, at 0-100° C. to generate the desired tertiary amine, see RC Larrock in “Comprehensive Organic Transformations-A Guide toFunctional Group Preparations”, VCH, (1989), pp 432-434, and referencescited therein.

[0362] Preferably the amide (1.0 eq) is treated with lithium aluminiumhydride (1.0-3 eq), at 0° C.-RT, in THF, for 1-24 hr, e.g.:

[0363] Process D

[0364] Oxidation

[0365] Aldehydes used in process B can be prepared using suitableoxidising agents; see R C Larrock in “Comprehensive OrganicTransformations-A Guide to Functional Group Preparations”, secondedition, (1999), pp 1234-1236 and 1238-1247, and references citedtherein.

[0366] Preferred oxidants are tetrapropylammonium perruthenate (Ley,et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods(Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-MartinPeriodinane reagent (Dess et al., J. Org. Chem., 1983, 48, 4155-4156).

[0367] Process E

[0368] Acid/amine salt coupling to give amides of formula XXXI

[0369] Either using an acid chloride+amine in a suitable solvent or theacid activated by a suitable agent, optionally in the presence of acatalyst, for example DMAP, in a suitable solvent; see R C Larrock in“Comprehensive Organic Transformations-A Guide to Functional GroupPreparations”, second edition, (1999), pp 1941-1949, and referencescited therein. Preferably the carboxylic acid (0.9-1.1 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HCl (1-1.5 eq) and1-hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15min and then the amine salt (1 eq) and base (NaHCO3 or organic base,Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr atRT.

[0370] For Example:

[0371] Process F

[0372] Urea Formation

[0373] Anilines can be converted to a urea using potassium cyanate(excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem.,1985, 28, 1427-1432. viz. reaction of the type:

[0374] Process G

[0375] Ester to an Alcohol

[0376] Esters can be converted to the corresponding alcohol using asuitable reducing agent, see Larock, Comprehensive OrganicTransformations-A Guide to Functional Group Preparations, secondedition, (1999), pp 1117-1120 and references cited therein. Suitablereducing agents include diisobutylaluminium hydride (DIBAL, seeWinterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride(LiAlH4, see Brown, Org. Reactions, 1951, 6, 469).viz. reaction of thetype:

[0377] Process H

[0378] Acid to Alcohol

[0379] It should be appreciated that the alcohols used in process D canbe prepared from the corresponding acid using a suitable reducing agent;see Larock, Comprehensive Organic Transformations-A Guide to FunctionalGroup Preparations, second edition, (1999), pp 1114-1116. Preferably thereducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38,2786), or LiAlH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C., for 1-24 hr.

[0380] Process I

[0381] Alcohol to Halide

[0382] It should be appreciated that the R⁴Lg used in Process A can beprepared from the corresponding alcohol R^(4a)OH.

[0383] Direct methods to prepare alkyl halides and alkyl sulphonatesfrom their alcohols are described by R C Larock, Comprehensive OrganicTransformations-A Guide to Functional Group Preparations, secondedition, (1999), pp 689-700, and references cited therein.

[0384] Process J

[0385] Benzyl Halides to Benzyloxyalcohols

[0386] Benzyloxyalcohols can be prepared by refluxing the appropriatebenzyl halide with sodium or sodium hydride and a polymethylene glycolin xylene, see J. Am. Chem. Soc., 1951, 3159-3162.viz. reaction of thetype:

[0387] Process K

[0388] Acetals to Benzyloxyalcohols

[0389] Acetals can be treated with a suitable reducing agent in thepresence of a Lewis acid or organic acid to give the benyloxyalcohols.

[0390] For representative examples see Organic Preparations andProcedures, Int., 1991, 23, 4, 427-431, ZrCl4/LiAlH4; J. Org. Chem.,1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic Preparations andProcedures, Int., 1985, 17(1), 11-16, NaBH4/TFA.viz. reaction of thetype:

Precursor(s) Example Name Coupling method —(CH2)nO(CH2)nR examples

N-(3-{6-ethyl-3-[2-(2- hydroxyethoxy)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-[3-(3-{2-[2- (dimethylamino)ethoxy]ethyl}-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

2-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]acetamide

N-(3-{6-ethyl-3-[2-(2- pyridinylmethoxy)ethyl]-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2-(2,2,2- trifluoroethoxy)ethyl]-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2-(2- propynyloxy)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{3-[2-(allyloxy)ethyl]- 6-ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2-(2- methoxyethoxy)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{3-[2- (cyclohexylmethoxy)ethyl]- 6-ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

(CH2)nO(CH2)nAr examples

N-[3-(3-{2-[(4- chlorobenzyl)oxy]ethyl}-6- ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

N-[3-(6-ethyl-3-{2-[(4- methoxybenzyl)oxy]ethyl}-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

All other (CH2)nO(CH2)nAr For a general procedure examples can beprepared via a 2 see; J. Am. Chem. Soc., step process from a benzyl1951, 3159-3162. alcohol or benzyl chloride Aryl substituents (mix. ofaryl and aryloxy examples):

2-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]benzamide

2-{4-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]phenyl}acetamide

N-(3-{3-[2-(4- aminophenoxy)ethyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-{3-[3-(2-{4- [(aminocarbonyl)amino]phenoxy}ethyl)-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl]phenyl}methanesulfonamide

N-(3-{3-[3-(4- acetylphenyl)propyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

4-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]benzenesulfonamide

N-[3-(6-ethyl-3-{2-[4- (methylsulfonyl)phenoxy]ethyl}-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

methyl 4-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]benzoate

ethyl {2-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]phenyl}acetate

methyl {4-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]phenoxy}acetate

N-[3-(6-ethyl-3-{2-[4- (hydroxymethyl)phenoxy]ethyl}-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

N-(3-{3-[2-([1,1′- biphenyl]-4-yloxy)ethyl]-6- ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-[3-(3-{2-[4-(4,5-dihydro- 1,3-oxazol-2- yl)phenoxy]ethyl}-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

N-(3-{6-ethyl-3-[2-(4- phenoxyphenoxy)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{3-[2- (benzyloxy)benzyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide Commercial aldehyde Processes B

N-(3-{3-[2-(4- benzylphenoxy)ethyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-{3-[3-(4-cyanobenzyl)- 6-ethyl-3- azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide Commercial aldehyde Process B

N-(3-{3-[2-(4- cyclopropylphenoxy)ethyl]- 6-ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

Substituents of the basic alkyl/alkenyl/alkynyl chains:

phenyl 3-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)propanoate

benzyl 4-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)butanoate

N-{3-[6-ethyl-3-(3-oxo-3- phenylpropyl)-3- azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

N-(3-{3-[3-(2,3-dihydro- 1H-inden-5-yl)-3- oxopropyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl benzoate

2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl cyanoacetate

2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1H-pyrazole-4- carboxylate

N-(3-{3-[(4-tert- butylcyclohexyl)methyl]-6- ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[(4- methoxycyclohexyl)methyl]-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-(3-{3-[(2- benzylcyclohexyl)methyl]- 6-ethyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-{3-[6-ethyl-3- (octahydro-1H-inden-2- ylmethyl)-3-azabicyclo[3.1.0]hex-6- yl]phenyl}methanesulfonamide

N-(3-{6-ethyl-3-[(2- phenylcyclopropyl)methyl]-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2- (phenylsulfonyl)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2- (ethylsulfonyl)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{3-[2- (benzylsulfonyl)ethyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl]benzenesulfonamide

N-[3-(6-ethyl-3-{2- [(methylsulfonyl)amino]ethyl}-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

N-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl]acetamide

N-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl]benzamide

N-[2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl]isonicotinamide

N-[3-(3-{2- [(anilinocarbonyl)amino]ethyl}-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide

ethyl 2-(6-ethyl-6-{3- [(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethylcarbamate

N-(3-{6-ethyl-3-[2- (phenylsulfanyl)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

N-(3-{6-ethyl-3-[2-(2- pyrimidinylsulfanyl)ethyl]-3-azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonamide

EXAMPLE 199:N-(3-{3-[3-(4-acetylphenyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide-andformate salt

[0391]

[0392] To a solution of the trifluoroacetic acid salt ofN-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (106mg, 0.27 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydrogencarbonate (90 mg, 1.1 mmol), 1-[4-(3-chloropropyl)phenyl]ethanone (58mg, 0.29 mmol) and sodium iodide (catalytic) and the reaction mixturewas heated at 70° C. for 20 h. After cooling, the solvent was removedin-vacuo to give a crude residue. This was purified by silica (14 g)column chromatography eluting with ethyl acetate:hexane (75:25) and thenwith neat ethyl acetate. Combination and evaporation of the appropriatefractions gave the partially purified product. This material was furtherpurified by preparative HPLC (condition 1) to afford the formate salt oftitle compound (16 mg, 12%) as a yellow oil.

[0393]¹H-NMR (300 MHz, CDCl₃, data for formate salt): 0.85 (t, 3H), 1.70(q, 2H), 2.05 (quintet, 2H), 2.15 (s, 2H), 2.55 (s, 3H), 2.70 (t, 2H),2.80-2.85 (m, 4H), 2.95 (s, 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1H),7.05-7.10 (m, 2H), 7.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s, 1H).

[0394] MS (Electrospray): M/Z (M−H) 439; C₂₅H₃₂N₂O₃S−H requires 439.2.

EXAMPLE 200:N-(3-{3-[2-(benzyloxy)benzyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[0395]

[0396] To a solution of 2-benzyloxybenzaldehyde (27 mg, 0.13 mmol) indichloromethane (5 ml) at room temperature was added the trifluoroaceticacid saltN-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction wasleft to stir at room temperature for 2 h. At this point sodiumtriacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reactionwas left to stir at room temperature for 16 h. Water (5 ml) was thenadded to the reaction mixture and the two layers were separated using aWhatman filter tube (hydrophobic polytetrafluoroethylene membrane). Theorganic layer was then blown down to dryness under a steam of nitrogen.The residue was purified by column chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting with hexane:ethylacetate (100:0, 1:1, 1:3, 1:6, 1:9 and 0:100) to afford the titlecompound (28 mg, 46%) as an oil.

[0397]¹H-NMR (300 MHz, CDCl₃): 0.85 (t, 3H), 2.80 (s, 2H), 2.00-2.10 (m,2H), 2.85 (d, 2H), 3.00 (s, 3H), 3.10-3.20 (dd, 2H), 3.80 (s, 2H), 5.10(s, 2H), 6.90-7.05 (m, 3H), 7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.40-7.50(m, 6H).

[0398] MS (Electrospray): M/Z (M+H) 477; C₂₈H₃₂N₂O₃S+H requires 477.

EXAMPLE 201:N-{3-[3-(4-cyanobenzyl)-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0399]

[0400] The compound above was prepared by a similar method to that ofExample 167, using the trifluoroacetic acid salt ofN-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (100mg, 0.25 mmol) and 4-cyanobenzaldehyde (33 mg, 0.25 mmol) as thestarting materials. The product was purified using preparative HPLC(conditions 3) to afford the title compound (28 mg, 28%) as an off-whitesolid.

[0401]¹H-NMR (300 MHz, CDCl₃): 0.85(t, 3H), 1.80 (s, 2H), 2.05 (q, 2H),2.80 (d, 2H), 3.00 (s, 3H), 3.10 (d, 2H), 3.70 (s, 2H), 7.00-7.20 (m,3H), 7.20 (m, 1H), 7.40 (d, 2H), 7.60 (d, 2H)

[0402] MS (Electrospray): M/Z (M+H) 396; C₂₂H₂₅N₃O₂S−H requires 396.

EXAMPLE 202N-(3-{3-[2-(4-cyclopropylphenoxy)ethyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[0403]

[0404] To a solution of the trifluoroacetic acid salt ofN-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (75mg, 0.19 mmol) in N,N-dimethylformamide (3 ml) was added sodium hydrogencarbonate (64 mg, 0.8 mmol), 1-(2-chloroethoxy)-4-cyclopropylbenzene (41mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) and the reactionmixture was heated at 60° C. for 20 h. After cooling, the solvent wasremoved in-vacuo to give a crude residue. This was purified bypreparative HPLC (condition 2) to afford the formate salt of the titlecompound (4 mg, 5%) as a brown gum.

[0405]¹H-NMR (300 MHz, CDCl₃, data for formate salt): 0.55-0.60 (m, 2H),0.80-0.95 (m, 5H), 1.80-1.90 (m, 3H), 2.25 (bs, 2H), 2.95 (s, 3H), 3.15(d, 2H), 3.45 (t, 2H), 3.80-3.90 (m, 2H), 4.20 (t, 2H), 6.90 (d, 2H),7.00 (d, 2H), 7.05-7.15 (t, 2H), 7.20 (s, 1H), 7.30 (t, 1H).

[0406] MS (Electrospray): M/Z (M−H) 439; C₂₅H₃₂N₂O₃S−H requires 439.2.

EXAMPLE 203:N-(3-{6-ethyl-3-[(2-phenylcyclopropyl)methyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[0407]

[0408] To a mixture of trans-2-phenylcyclopropylcarboxaldehyde {ref. J.Org. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and the trifluoroaceticacid salt ofN-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50mg, 0.13 mmol) in dry 1,2-dichloroethane was added Hunigs' base (0.02ml, 0.12 mmol). The mixture was sonicated for 3 minutes and then stirredfor a further 30 minutes followed by the addition of sodiumtriacetoxyborohydride (50 mg, 0.25 mmol). After stirring for 72 hours,the reaction was diluted with ethyl acetate (50 ml) and partitionedbetween saturated sodium bicarbonate (2×25 ml). The organic layer waswashed with brine (2×20 ml), dried over anhydrous sodium sulphate,filtered and the solvent evaporated under reduced pressure to produce ayellow/brown oil. This oil was dissolved in the minimum of quantity ofdichloromethane and purified using a Biotage™ 6 g cartridge eluting witha gradient of ethyl acetate:hexane (30:70) to ethyl acetate (100%) toafford the title compound (32 mg 62%) as an oil.

[0409]¹H-NMR (300 MHz, CDCl₃): 0.78-0.90 (m, 3H), 0.97 (m, 1H), 1.24 (m,1H), 1.72 (m, 1H), 1.76-1.79 (m, 2H) 1.90-2.05 (m, 2H) 2.45 (dd, 1H),2.60 (dd, 1H), 2.84-2.95 (m, 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H)6.89-7.3 (m, 9H).

[0410] MS (Electrospray): M/Z (M+H) 411; C₂₄H₃₀SO₂N₂+H requires 411

[0411] Preparations

[0412] NB Preparations 1 to 148 from International Patent Applicationpublication no. WO00/39089 are herein incorporated by reference in theirentirety, and the same numbering is adhered to herein.

Preparation 149 1-[4-(3-chloropropyl)phenyl]ethanone

[0413]

[0414] Aluminium chloride (15.0 g, 0.11 moles) and acetyl chloride (16.0g, 0.20 moles) were dissolved in dichloromethane (50 ml) at roomtemperature. This mixture was then added dropwise to a solution1-chloro-3-phenylpropane (15.5 g, 0.10 moles) in dichloromethane (25 ml)at room temperature over 15 minutes. The mixture was stirred for 1 hrand then poured cautiously onto ice. The aqueous layer was extractedwith dichloromethane (450 ml). The organics were washed with water andbrine, and then dried (MgSO₄) and concentrated in-vacuo to give thetitle compound (19.2 g, 98%) as an oil.

[0415]¹H-NMR (300 MHz, CDCl₃): 2.10 (quintet, 2H), 2.60 (s, 3H), 2.85(t, 2H), 3.55 (t, 2H), 7.30 (d, 2H), 7.90 (d, 2H).

[0416] MS (thermospray): M/Z [M+NH4]⁺ 214; C₁₁H₁₃ClO+NH₄ requires 214.1.

Preparation 150 1-(2-chloroethoxy)-4-cyclopropylbenzene

[0417]

[0418] 4-Cyclopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et.al., Org. Prep. Proceed. Int., 1992, 24 (6), 696-698), 2-chloroethylp-toluenesulfonate (17.71 g, 75.5 mmol), and potassium carbonate (10.4g, 75.4 mmol) in anhydrous acetonitrile (500 ml) were stirred togetherunder a nitrogen atmosphere at reflux for 30 hours. The reaction wasallowed to cool to room temperature and diluted with ethyl acetate (1000ml). The organics were washed with water (3×250 ml), dried (MgSO4),filtered and concentrated in vacuo. This crude material was purified bysilica column chromatography eluting with hexane:dichloromethane (4:1)and then with hexane:dichloromethane (3:1) to afford the title compound(8.7 g, 88%) as a solid.

[0419] Mpt: 47-48° C.

[0420]¹H-NMR (300 MHz, CDCl₃): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H),1.80-1.95 (m, 1H), 3.81 (t, 2H), 4.21 (t, 2H), 6.82 (d, 2H), 7.02 (d,2H).

[0421] MS (thermospray) M/Z (M) 196; C₁₁H₁₃OCl requires 196.1.

Preparation 151 1-Allyl-1H-pyrolle-2,5-dione (see J. Org. Chem., 1997,62, 2652)

[0422]

[0423] To a solution of maleic anhydride (98 g, 1.00 mol) in dry toluene(3000 ml) at room temperature under a nitrogen atmosphere was addeddropwise a solution of allylamine (57.1 g, 1.00 mol) in toluene (1000ml) over one hour. The mixture was stirred at room temperature for 20hours and then zinc chloride (136.3 g, 1.00 mol) was added and thereaction was heated to 80° C. 1,1,1,3,3,3-Hexamethyldisilazane (242 g,1.5 mol) in toluene (1000 ml) was then added dropwise over one hour andthe mixture was stirred at 80° C. for another 4 hours. The mixture wascooled to room temperature and then poured onto 1N HCl (4000 ml). Thetwo layers were separated and the organic layer was washed with water(2000 ml), saturated sodium bicarbonate (2000 ml) and brine (2000 ml).The organics were concentrated in vacuo to give the title compound (74g, 54%) as a solid.

[0424]¹H-NMR (300 MHz, CDCl₃): 4.05 (d, 2H), 5.00-5.15 (m, 2H),5.60-5.80 (m, 1H), 6.65 (2H, s).

Preparation 152 1-(3-nitrophenyl)-1-propanone hydrazone

[0425]

[0426] To a solution of 3-nitropropiophenone (168 g, 0.93 mol) inethanol (830 ml) at room temperature was slowly added hydrazinemonohydrate (96.8 g, 1.93 mol) via a dropping funnel. The reactionmixture was heated at reflux for 4 hours and then cooled to roomtemperature. The solvent was removed in vacuo and the residue waspartitioned between dichloromethane (750 ml) and water (750 ml). The twolayers were separated and the organic layer was washed with brine (250ml), dried (Na2SO4), filtered and concentrated in-vacuo to give anorange oil. This residue was crystallised from diisopropyl ether at −20°C. to afford the title compound (110 g, 61%) as a yellow crystallinesolid.

[0427] Mpt: 32° C.

[0428]¹H-NMR (300 MHz, CDCl₃): 1.20 (t, 3H), 2.70 (q, 2H), 5.65 (broads, 2H), 7.50 (t, 1H), 7.95 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H).

[0429] MS (Electrospray) M/Z [MH]⁺194; C₉H₁₁N₃O₂+H requires 194.1.

Preparation 1533-Allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0430]

[0431] To a stirred solution of 1-(3-nitrophenyl)-1-propanone hydrazone(84.7 g, 439 mmol) in 1,4-dioxane (1000 ml) was rapidly added manganesedioxide (grade CMD-1 from Sumitromo, 175 g, 2.01 mol) followed by asaturated solution of ethanolic potassium hydroxide (40 ml) at roomtemperature. The mixture was stirred at room temperature for 18 minutesand during this period the reaction temperature had risen from 19° C. to25° C. Stirring was then stopped and the mixture was allowed to settle.This mixture was then filtered through a pad of Celite® dropwise,directly into a solution of 1-allyl-1H-pyrolle-2,5-dione (57.3 g, 418mmol) in 1,4-dioxane (200 ml). The Celite® pad was washed with1,4-dixane (100 ml) to ensure complete addition of the reactants. Afterstirring at room temperature for one hour the mixture was heated atreflux for 20 hours. The mixture was cooled to room temperature and thesolvent was removed in vacuo. The residue was then crystallised fromdiisopropyl ether (1000 ml) at 0° C. to afford the title compound (83 g,66%) as an off-white crystalline solid.

[0432] MPt: 128-129° C.

[0433]¹H-NMR (300 MHz, CDCl₃): 0.90 (t, 3H), 1.80 (q, 2H), 2.80 (s, 2H),4.05 (d, 2H), 5.20 (d, 1H), 5.30 (d, 1H), 5.75-5.85 (m, 1H), 7.55 (t,1H), 7.70 (dd, 1H), 8.20 (dd, 1H), 8.25 (d, 1H).

Preparation 1543-allyl-6-(3-aminophenyl)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0434]

[0435] To a stirred suspension of3-allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(93 g, 310 mmol) and iron powder (151 g, 2.70 mol) in ethanol (6.75 L)was added calcium chloride (16.7 g, 0.15 mol) in water (1.2 L). Themixture was heated at reflux for three hours and then cooled to roomtemperature before being filtered through Celite®. The filtrate wasconcentrated in vacuo to give a wet solid. This material was dissolvedin dichloromethane (500 ml) and the two layers were separated. Theorganic layer was dried (MgSO4), filtered and concentrated in vacuo togive a pale yellow solid (81 g). This material was crystallised fromethyl acetate and hexane (1:1; 6 ml per gram) at room temperature toafford the title compound (54 g, 65%) as a pale yellow crystallinesolid.

[0436]¹H-NMR (300 MHz, CDCl₃): 0.90 (t, 3H), 1.75 (q, 2H), 2.75 (s, 2H),3.95 (broad s, 2H), 4.05 (d, 2H), 5.25 (d, 1H), 5.35 (d, 1H), 5.75-5.85(m, 1H), 6.65 (d, 1H), 6.70 (s, 1H), 6.75 (d, 1H), 7.10 (t, 1H).

Preparation 155 3-(3-Allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniline

[0437]

[0438] To a solution of lithium aluminium hydride (1M solution in THF;400 ml, 400 mmol) in tetrahydrofuran (400 ml) under a nitrogenatmosphere at −15° C. was added3-allyl-6-(3-aminophenyl)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione(44 g, 163 mmol) in tetrahydrofuran (250 ml) via a dropping funnel over0.5 hours. The mixture was then allowed to slowly warm to roomtemperature over one hour. The mixture was heated at 50° C. for 3 hoursand then cooled to 5° C. Water (400 ml) was then cautiously added to thecooled (5° C.) reaction mixture. The solids were removed by filtrationthrough a pad of Celite®, washing with ethyl acetate (400 ml). Thefiltrate was dried (MgSO₄), filtered, and concentrated in vacuo toafford the title compound (38.1 g, 96%) as a golden oil.

[0439]¹H-NMR (300 MHz, CDCl₃): 0.85 (t, 3H), 1.80-1.95 (m, 4H),2.85-3.00 (m, 4H), 3.15 (d, 2H), 3.60 (broad s, 2H), 5.10 (d, 1H), 5.20(d, 1H), 5.80-5.95 (m, 1H), 6.50 (d, 1H), 6.60 (s, 1H), 6.65 (d, 1H),7.05 (t, 1H).

[0440] MS (AP⁺) M/Z [MH]⁺243; C₁₆H₂₂N₂+H requires 243.2.

Preparation 156N-[3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide

[0441]

[0442] To a solution of3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (41 g, 169 mmol)and triethylamine (34 g, 337 mmol) in dichloromethane (750 ml) at −40°C. was added dropwise methanesulfonyl chloride (23.7 g, 206 mmol) via adropping funnel. The reaction mixture was slowly allowed to warm to roomtemperature over 2 hours and was then stirred at room temperature for 20hours. The organics were then washed with water (4×500 ml), dried(MgSO₄), filtered and concentrated in vacuo to afford the title compound(59.0 g) as a crude gum.

[0443]¹H-NMR (300 MHz, CDCl₃): 0.85 (t, 3H), 1.85 (s, 2H), 1.95 (q, 2H),2.80-3.20 (m, 9H), 5.10-5.25 (m, 2H), 5.80-5.95 (m, 1H), 7.00-7.40 (m,4H).

Preparation 157N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide

[0444]

[0445] To a degassed solution ofN-[3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(54.0 g, 169 mmol) and 1,3-dimethylbarbituric acid (80.0 g, 512 mmol) indichloromethane (500 ml) under a nitrogen atmosphere was addedtetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol). Themixture was heated at reflux for 8 hours and then stirred at roomtemperature for 20 hours. The organics were then extracted with 2M HCl(2×100 ml) and water (100 ml). The combined aqueous layers were thenwashed with dichloromethane (4×100 ml) and freeze dried to give a crudesolid. This material was purified by preparative HPLC (condition 4) toafford the trifluoroacetic acid salt of title compound (25.2 g, 53%) asa grey solid.

[0446]¹H-NMR (300 MHz, CD₃OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m,2H), 2.90 (s, 3H), 3.25-3.35 (m, 2H), 3.70-3.80 (m, 2H), 7.10-7.15 (m,2H), 7.20 (s, 1H), 7.30 (t, 1H).

[0447] MS (AP+): M/Z [MH]⁺ 281; C14H20N2O2S+H requires 281.1.

Preparation 158:3-Benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0448] To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone

[0449] (100 g, 0.56 mol), in dioxan (1 L) was added MnO₂ (350 g, 2.3mol) and the reaction mixture stirred at room temperature for 30 mins.The slurry was filtered through celite and the celite pad washed withdioxan (200 mls). The filtrate was returned to a pot and N-benzylmaleimide (110 g,) added portionwise over a period of 20 mins. Thereaction mixture was stirred at room temperature for 4 hrs before beingheated under reflux for 16 hrs. The reaction mixture was cooled to roomtemperature and the solvent removed in vacuo. The residue was trituratedin methanol (500 mls) and the product isolated by filtration as a whitecrystalline solid (56%).

[0450] NMR (CDCl₃) d: 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H), 4.63 (s,2H), 7.28-7.34 (m, 3H), 7.43-7.45 (d, 2H), 7.52-7.56 (t, 1H), 7.63-7.65(d, 1H), 8.13-8.16 (d, 1H), 8.17 (s, 1H)

[0451] MS (APCI): m/z [MH+] 337.5 +H requires 337.3

Preparation 1596-(3-Aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0452] To a slurry of3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(30 g, 89 mmol) in ethyl acetate (600 mls) was added 5%Pt/C (1.5 g, 5 wt%). The mixture was hydrogenated at 4 atm. (=60 p.s.i.)/room temperaturefor 18 hrs. The slurry was filtered through arbacel and the resultingsolution evaporated in vacuo to yield the product as a white crystallinesolid (24 g, 88%).

[0453] NMR (CDCl3) d: 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, bs), 4.60 (s,2H), 6.56-6.58 (d, 1H), 6.60 (s, 1H), 6.65-6.67 (d, 1H), 7.07-7.11 (t,1H), 7.26-7.33 (m, 3H), 7.42-7.44 (m, 2H).

[0454] MS (APCI): m/z [MH+] 307.5 +H requires 307.4

Preparation 160:N-{3-[3-Benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0455] To a solution of6-(3-aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione(24 g, 78 mmol) in ethyl acetate (480 mls) was added pyridine (9.5 mls,118 mmol) followed by the slow addition of methane sulfonyl chloride(9.1 mls, 118 mmol). The reaction was stirred at room temperature for2.5 hrs. The reaction mixture was washed sequentially with 1M HClsolution (120 mls) and water (120 mls). The ethyl acetate was dried overMgSO₄ and evaporated in vacuo to yield the product as an orange solid(30 g, 99%).

[0456] NMR (CDCl3) d: 1.27 (s, 3H), 2.77 (s, 2H), 3.02 (s, 3H), 4.61 (s,2H), 7.08-7.14 (m, 3H), 7.26-7.32 (m, 4H), 7.41-7.42 (d, 2H).

[0457] MS (APCI): m/z [MH+] 385.7 +H requires 385.5

Preparation 161:N-{3-Benzyl-6-methyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0458] To a solution ofN-{3-[3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(150 g, 391 mmol), under nitrogen was added sodium borohydride (31 g,820 mmol). The reaction mixture was cooled to <10° C. and the BF₃.OEt₂(138.6 mls, 1094 mmol) added dropwise maintaining the temperature at<10° C. The reaction mixture was allowed to warm to room temperatureover 2 hrs before being heated under reflux for a further 8.5 hrs. Thereaction mixture was cooled to between 0° C. and 50° C. and an aqueoussolution of piperazine (198.5 g, 2304 mmol in 1.26 L of water) added.The reaction mixture was then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate (900 mls) added,and the phases were separated. The aqueous phase was extracted with asecond portion of ethyl acetate (450 mls). The organic phases werecombined and washed with water (750 mls). The organics were dried overMgSO₄ and evaporated in vacuo to yield the product as a whitecrystalline solid (129 g, 93%).

[0459] NMR (CDCl3) d: 2.62 (s, 3H), 2.80-2.83 (d, 2H), 2.99 (s, 3H),3.03-3.07 (d, 2H), 3.68 (s, 2H), 7.01-7.02 (s, 1H), 7.06-7.08 (m, 2H),7.22-7.26 (m, 3H), 7.30-7.32 (m, 2H).

[0460] MS (APCI): m/z [MH+]357.5 +H requires 357.5

Preparation 162:N-{3-[6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0461] To a solution ofN-{3-benzyl-6-methyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(20 g, 56 mmol), in methanol, was added ammonium formate (10.6 g, 168mmol) and the reaction stirred for 5 minutes. 10% Pd/C (8 g) was addedand the resulting mixture heated at reflux for 16 hrs. The mixture wasallowed to cool and the catalyst removed by filtration through celite.The solvent was removed in vacuo to yield the product as a pale yellowoil, which solidified on standing (15.2 g, 85%).

[0462] NMR (CDCl3) d: 1.27 (s, 3H), 1.85-1.88 (d, 2H), 2.93 (s, 3H),3.07-3.10 (d, 2H), 3.39-3.44 (d, 2H), 6.92-6.97 (m, 2H), 7.06 (s, 1H),7.20-7.23 (m, 1H).

[0463] MS (APCI): m/z [MH+] 267.4 +H requires 267.3

Preparation 163:3-Benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0464] To a solution of 1-(3-nitrophenyl)-1-propanone hydrazone

[0465] (42.1 gg, 217 mmol), in dioxan (630 mls) was added MnO₂ (126 g,1440 mmol) and the reaction mixture stirred at room temperature for 20mins. The slurry was filtered through celite and the celite pad washedwith dioxan (200 mls). The filtrate was returned to a pot and N-benzylmaleimide (44.9 g, 239 mmol) added portionwise over a period of 20 mins.The reaction mixture was stirred at room temperature for 60 hrs beforebeing heated under reflux for 16 hrs. The reaction mixture was cooled toroom temperature and the solvent removed in vacuo. The residue washeated to reflux in methanol (1200 mls) for 3 hours and then cooled toroom temperature. The product was isolated by filtration as a whitecrystalline solid (42.4 g, 56%).

[0466] NMR (CDCl3) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H), 2.78 (s,2H), 4.64 (s, 2H), 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1H), 7.52-7.55 (t,1H), 7.62-7.65 (d, 2H), 8.17-8.18 (n, 3H).

[0467] MS (APCI): m/z [MH+] 351.5 +H requires 351.3

Preparation 164:6-(3-Aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0468] To a slurry of3-benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(42.1 g, 120 mmol) in ethyl acetate (850 mls) was added 5%Pt/C (2.1 g, 5wt %). The mixture was hydrogenated at 60 psi/ room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solutionevaporated in vacuo to yield the product as a white crystalline solid(34.1 g, 89%).

[0469] NMR (CDCl3) d: 0.70-0.74 (t, 3H), 1.41-1.47 (q, 2H), 2.73 (s,2H), 3.68 (bs, 2H), 4.61 (s, 2H), 6.55-6.57 (d, 1H), 6.60 (s, 1H),6.66-6.68 (d, 1H), 7.07-7.10 (t, 1H), 7.28-7.32 (m, 3H), 7.41-7.43 (d,2H).

[0470] MS (APCI): m/z [MH+] 321.4 +H requires 321.4

Preparation 165:N-{3-[3-Benzyl-6-ethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0471] To a solution of6-(3-aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione(31.5 g, 98 mmol) in dichloromethane (250 mls) was added pyridine (9.5mls, 118 mmol) followed by the slow addition of methane sulfonylchloride (9.1 mls, 118 mmol). The reaction was stirred at roomtemperature for 16 hrs. The reaction mixture was washed sequentiallywith 1M HCl solution (250 mls) and water (120 mls). The dichloromethanewas dried over MgSO₄ and evaporated in vacuo to yield the product as awaxy pink solid (38.2 g, 98%).

[0472] NMR (CDCl3) d: 0.68-0.72 (t, 3H), 1.42-1.47 (q, 2H), 2.75 (s,2H), 3.02 (s, 3H), 4.62 (s, 2H), 7.13-7.18 (m, 3H), 7.29-7.42 (m, 4H),7.41-7.43 (d, 2H).

[0473] MS (APCI): m/z [MH+] 399.6 +H requires 399.5

Preparation 166:N-{3-Benzyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0474] To a solution ofN-{3-[3-benzyl-6-ethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(38.2 g, 95 mmol), in THF (200 mls) under nitrogen was added sodiumborohydride (7.46 g, 201 mmol). The reaction mixture was cooled to <10□C. and the BF₃.OEt₂ (38.1 mls, 268 mmol) added dropwise maintaining thetemperature at <10□ C. The reaction mixture was allowed to warm to roomtemperature over 2 hrs before being heated under reflux for a further 12hrs. The reaction mixture was cooled to between 0° C. and 5° C. and anaqueous solution of piperazine (48.7 g, 565 mmol in 320 mls of water)added. The reaction mixture was then heated under reflux for a period of18 hrs. The THF was removed under vacuum, ethyl acetate (200 mls) added,and the phases were separated. The aqueous phase was extracted with asecond portion of ethyl acetate (200 mls). The organic phases werecombined and washed with 3 separate portions of water (3×400 mls). Theorganics were dried over MgSO₄ and evaporated in vacuo to yield theproduct as a white crystalline solid (33.5 g, 94%).

[0475] NMR (CDCl3) d: 0.84-0.88 (t, 3H), 1.76-1.77 (d, 2H), 2.06-2.12(q, 2H), 2.79-2.81 (d, 2H), 2.99 (s, 3H), 3.06-3.08 (d, 2H), 3.67 (s,2H), 7.01-7.03 (d, 1H), 7.08-7.10 (d, 2H), 7.22-7.26 (m, 3H), 7.30-7.32(m, 3H).

[0476] MS (APCI): m/z [MH+] 371.3 +H requires 371.5

Preparation 167N-{3-[6-Ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[0477] To a solution ofN-{3-benzyl-6-ethyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(500 mg, 1.34 mmol), in methanol (30 mls), was added ammonium formate(255 mg, 4.05 mmol) and the reaction stirred for 5 minutes. 10% Pd/C(200 mg) was added and the resulting mixture heated at reflux for 2 hrs.The mixture was allowed to cool and the catalyst removed by filtrationthrough celite. The solvent was removed in vacuo to yield the product asa pale yellow oil, which solidified on standing (15.2 g, 85%).

[0478] NMR (CDCl3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.82-1.86(d, 2H), 2.98 (s, 3H), 3.12-3.18 (d, 2H), 3.21-3.26 (d, 2H), 7.01-7.06(d, 1H), 7.10-7.14 (m, 2H), 7.25-7.28 (m, 1H).

[0479] MS (APCI): m/z [MH+]281.7 +H requires 281.4

[0480] Other building block materials useful in synthesising compoundsof formula (I) with various different R⁴ groups are available from thesources indicated in the table below, and routine derivatisationthereof, or analogy synthesis. Example of R⁴ Substructure commercialsource Literature reference —(CH2)nO(CH2)nR examples

ALDRICH

ALDRICH

SALOR

1. Org. Magn. Reson., 1975, Vol 7, 488-495.

WO 8707270 Alcohol US 5157159

MAYBRIDGE

ALDRICH

ALDRICH

Bull. Soc. Chim. Fr.; 1947, 616. Alcohol-EP-0811621 (CH2)nO(CH2)nArylexamples

BIONET

1. J. Org. Chem., 1987, 52 (12), 2594. 2. Org. Prep. Proceed. Int; 23,4; 1991, 427. All other (CH2)nO(CH2)nAryl For a general examples couldbe prepared procedure see; J. Am. via 2 step process from a Chem. Soc.,1951, 3159- benzyl alcohol or benzyl 3162. chloride Aryl substituents onR⁴ (mix. of aryl and aryloxy examples):

SALOR J. Med. Chem., 1985, 28, 1427.

J. Med. Chem., EN; 28, 10, 1985, 1427.

SALOR

By manipulation of the product above.

DE 2135678; DE 3636333 Rev. Med.-Chiv., 1985, 89 (2), 316-20.

SPECS

APIN J. Med. Chem., 28, 10, 1985, 1427

J. Med. Chem., 28, 10, 1985, 1427

EP-0171760 J. Med. Chem., 28, 10, 1985, 1427.

LANCASTER

ICN-RF

MAYBRIDGE

SALOR

MAYBRIDGE

Agric. Biol. Chem., 1978, 1767. WO 9611192 (alcohol) WO 9610999Imidazole analogue: J. Med Chem., 1981, 24(10), 1139 US-4713387

MAYBRIDGE J. Med. Chem., 28, 10, 1985, 1427. Substituents of the basicR⁴ alkyl/alkenyl/alkynyl chains:

ICN-RF

WYCHEM

ALDRICH

SALOR

ALDRICH

J. Am. Chem. Soc., 78, 1956, 4944. Alcohol: EP-136260

SALOR

ALDRICH

ALDRICH

SALOR

J. Org. Chem., 1954, 1449.

ALDRICH

LANCASTER Alcohol-ALDRICH

LANCASTER

LANCASTER

SPECS

MDA

ALDRICH

ALDRICH MAYBRIDGE

ALDRICH

MAYBRIDGE

SALOR

ALDRICH

ALDRICH

1. A substance which is a compound of formula I,

wherein the “Ar” ring represents an optionally benzo-fused phenyl or 5-or 6-membered heteroaryl ring; R¹ when taken alone is H, halogen, NO₂,NH₂, NY²WY¹, Het¹, AD, CO₂R⁷, C(O)R⁸, C(═NOH)R⁸, or OE, Y² is H, C₁₋₆alkyl, C₃₋₆ alkenyl (each of which alkyl and alkenyl is optionallysubstituted by aryl, aryloxy or Het¹), W is SO₂, CO, C(O)O, P(Y¹)═O,P(Y¹)═S, Y¹ is C₁₋₁₀ alkyl (optionally substituted by one or moresubstituents independently selected from halogen, OH, C₁₋₄ alkoxy, C₁₋₆alkanoyloxy, CONH₂, C₁₋₆ alkoxycarbonyl, NH₂, aryl, mono- or di(C₁₋₄alkyl)amino, C₃₋₈ cycloalkyl, phthalimidyl, Het¹), Het¹, aryl(optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and halogen), NH₂, N(C₁₋₆alkyl)₂ or NH(C₁₋₆ alkyl), Het¹ is a heterocyclic group containing up to4 heteroatoms selected from N, O and S, which may comprise up to 3 rings(preferably a heteroaryl group, optionally benzo- or pyrido-fusedheteroaryl), optionally substituted by one or more substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₃₋₆ halocycloalkyl, ═O, OH, halogen,NO₂, SiR^(19a)R^(19b)R^(19c), CON^(20a)R^(20b), NR^(20a)R^(20b),SR^(21a), NR^(21b)SO₂R^(22a), NR^(21c)C(O)OR^(22b), NR^(21d)COR^(22d),and C₁₋₆ alkoxycarbonyl, and if a S atom is present in a ring, it can bepresent as part of a —S—, S(O)— or —S(O₂)— group, and carbon atoms inthe ring can be present as a part of a carbonyl moiety; R^(19a),R^(19b), R^(19c) each independently represent C₁₋₆ alkyl or aryl,R^(20a) and R^(20b) each independently represent H, C₁₋₆ alkyl, aryl,(C₁₋₄ alkyl)phenyl, each of which alkyl, aryl and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,NH₂ and/or halogen, or R^(20a) and R^(20b) can be taken together withthe N atom to which they are attached, to form a 4- to 6-membered ringoptionally substituted by one or more substitutuents independentlyselected from one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, ═O, NO₂, NH₂and/or halogen, R^(21a, b, c and d) each independently represent H, C₁₋₆alkyl, aryl or C₁₋₄ alkylphenyl, each of which alkyl, aryl, andalkylphenyl are optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄alkoxy, OH, NO₂, halogen, NH₂, R^(22a, b, and c) band each independentlyrepresent C₁₋₆ alkyl, aryl or C₁₋₄ alkylphenyl, each of which alkyl,aryl, and alkylphenyl are optionally substituted by one or more C₁₋₄alkyl, C₁₋₄ alkoxy, OH, NO₂, halogen, NH₂, A is C₁₋₄ alkylene, C₂₋₄alkenylene or C₂₋₄ alkynylene, each of which is optionally substitutedby one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen and/or OH, D is H, OH,CN, NR²⁵R²⁶, CONR²⁵R²⁶, NHR²⁷, CO₂R²⁸, COR²⁹, C(═NOH)R²⁹, or AD is CN,NR²⁵R²⁶, CONR²⁵R²⁶, where R²⁵ and R²⁶ are either each independently H,C₁₋₃ alkyl, C₃₋₈ cycloalkyl, aryl, C₁₋₄ alkylphenyl (each of which C₁₋₃alkyl, C₃₋₈ cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionallysubstituted by one or more NO₂, halogen, C₁₋₄ alkyl and/or C₁₋₄ alkoxy,(each of which latter C₁₋₄ alkyl and C₁₋₄ alkoxy is optionallysubstituted by one or more halogen)), or R²⁵ and R²⁶ are taken togetherwith the N atom to which they are attached and can form a 4- to7-membered heterocyclic ring optionally incorporating one or morefurther hetero atoms selected from N, O and S, and which ring isoptionally substituted by one or more C₁₋₄ alkyl, OH, ═O, NO₂, NH₂and/or halogen, R²⁷ is COR³⁰, CO₂R^(31a), SO₂R^(31b), R²⁸ and R²⁹ areeach independently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl orC₁₋₄alkylphenyl, each of which C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl andC₁₋₄ alkylphenyl are optionally substituted by one or more NO₂, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy (each of which latter C₁₋₄ alkyl and C₁₋₄ alkoxyare optionally substituted by one or more halogen), R³⁰ is H, C₁₋₄alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyloxy, aryl, aryloxy,C₁₋₄ alkylphenyl, phenyl(C₁₋₄)alkoxy, (each of which C₁₋₄ alkyl, C₃₋₈cycloalkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyloxy, aryl, aryloxy, C₁₋₄alkylphenyl and phenyl(C₁₋₄)alkoxy are optionally substituted by one ormore NO₂, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy (which latter alkyl andalkoxy are optionally substituted by one or more halogen)), R^(31a) andR^(31b) are each independently C₁₋₄ alkyl, C₃₋₈ cycloalkyl, aryl or C₁₋₄alkylphenyl, each of which is optionally substituted by one or more NO₂,halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy, each of which latter alkyl andalkoxy is optionally substituted by one more halogen E is H, CONR³²R³³,CSNR³²R³³, COR³⁴, CO₂R³⁴, COCH(R^(34a))NH₂, R³⁵, CH₂CO₂R^(35a),CHR^(35b)CO₂R^(35a), CH₂OCO₂R^(35c), CHR^(35d)OCO₂R^(35c),COCR³⁶═CR³⁷NH₂, COCHR³⁶CHR³⁷NH₂, or PO(OR³⁸)₂, R³² and R³³ are eachindependently H, C₃₋₁₀ alkylalkenyl, C₃₋₇ cycloalkyl (optionallysubstituted by C₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n)),C₁₋₁₀ alkyl (optionally substituted by C₄₋₇ cycloalkyl (optionallysubstituted by C₁₋₄ alkyl) or phenyl optionally substituted by (X)_(n)),or R³² and R³³ can be taken together with the N atom to which they areattached and can form a 5- to 8-membered heterocycle optionallycomprising further hetero atoms selected from N, O and S, whichheterocycle is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by one or more halogen, R³⁴ is H, C₄₋₇ cycloalkyl(optionally substituted by one or more C₁₋₄ alkyl), phenyl (optionallysubstituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH),or C₁₋₆ alkyl (optionally substituted by one or more halogen, C₄₋₇cycloalkyl (optionally substituted by one or more C₁₋₄ alkyl), or phenyl(optionally substituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³and/or OH)), R^(34a) is H, C₁₋₆ alkyl (optionally substituted by one ormore halogen, C₄₋₇ cycloalkyl (optionally substituted by one or moreC₁₋₄ alkyl), or phenyl (optionally substituted by (X)_(n), C₁₋₄alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH)), C₄₋₇ cycloalkyl (optionallysubstituted by one or more C₁₋₄ alkyl), phenyl (optionally substitutedby (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH) or anaturally occuring amino acid substituent, R³⁵ is C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, phenyl (optionallysubstituted by one or more (X)_(n), C₁₋₄ alkanoyl, NHR³², CON(R³²)₂,and/or OH), C₁₋₆ alkyl (optionally substituted by C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, or phenyl (optionallysubstituted by one or more (X)_(n), C₁₋₄ alkanoyl, NHR³², CON(R³²)₂,and/or OH)), C₁₋₄ alkoxy(C₁₋₄ alkyl), phenyl(C₁₋₄)alkyloxy(C₁₋₄)alkyl,tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,R^(35a,b,c and d) are each independently H, C₄₋₇ cycloalkyl optionallysubstituted by one or more C₁₋₄ alkyl, phenyl optionally substituted byone or more (X)_(n) or C₁₋₆ alkyl (optionally substituted by C₄₋₇cycloalkyl optionally substituted by one or more C₁₋₄ alkyl, or phenyloptionally substituted by one or more (X)_(n)), R³⁶ and R³⁷ eachindependently represent H, C₃₋₆ alkylalkenyl, C₄₋₇ cycloalkyl, phenyloptionally substituted by one or more (X)_(n), or C₁₋₆ alkyl (optionallysubstituted by C₄₋₇ cycloalkyl optionally substituted by one or moreC₁₋₄ alkyl, or phenyl optionally substituted by one or more (X)_(n)),R³⁸ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄ alkyl,phenyl optionally substituted by one or more (X)_(n), or C₁₋₆ alkyl(optionally substituted by C₄₋₇ cycloalkyl optionally substituted by oneor more C₁₋₄ alkyl, or phenyl optionally substituted by one or more(X)_(n)), R² when taken alone is H or halogen; or R¹ and R², whenattached to adjacent carbon atoms, can be taken together with the carbonatoms to which they are attached, and may represent Het^(1a); Het^(1a)is a heterocyclic group containing up to 4 heteroatoms selected from N,O and S, which may comprise up to 3 rings (and is preferably anoptionally benzo-fused 5- to 7-membered heterocyclic ring) and whichgroup is optionally substituted by one or more substituentsindependently selected from OH, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy, which C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted by oneor more C₃₋₆ cycloalkyl, aryl(C₁₋₆)alkyl, which aryl group is optionallysubstituted by one or more halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy, which latter C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted byone or more NR²³R²⁴, NR²³S(O)_(n)R²⁴, NR²³C(O)_(m)R²⁴, and if a S atomis present in a ring, it can be present as part of a —S—, S(O)— or—S(O₂)— group, which R²³ and R²⁴ when taken alone independentlyrepresent H, C₁₋₄ alkyl, or C₁₋₄ haloalkyl, or R²³ and R²⁴ can be takentogether with the N atom to which they are attached, to form a 4- to6-membered heterocyclic ring optionally comprising one or more furtherheteroatoms selected from, N, O, or S, and which heterocyclic ring isoptionally substituted by one or more halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy and/or C₁₋₄ haloalkoxy groups, R³ is H, CN,halogen, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₂₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl, saturated heterocycle, NR¹²R¹³, CONR¹²R¹³,NY²WY¹, C₁₋₆ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkenyl, (each of which alkyl,alkenyl and alkynyl groups is optionally substituted by one or more CN,halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy,C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy,C₄₋₉ cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle,NR¹²R¹³, CONR¹²R¹³ and/or NY²WY¹), R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl orC₃₋₁₀ alkynyl, each of which groups is linked to the N atom via a sp³carbon, and which group is substituted by one or more substituentsselected from: C₂₋₆ alkoxy [substituted by one or more groups selectedfrom OH, NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄ alkynyl, C₂₋₄alkenyl, heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹), CO(aryl¹),CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹), CO₂CH₂(aryl¹),CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl¹),S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹], S(O)_(n)C₁₋₆ alkyl[optionally substituted by one or more groups selected from OH, NR²⁵R²⁶,CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄ alkynyl, C₂₋₄ alkenyl,heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹), CO(aryl¹),CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹), CO₂CH₂(aryl¹),CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl¹),S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹], aryl²,CO₂CH₂(heteroaryl¹), CO₂CH₂(aryl¹), cycloalkyl¹, CO(heteroaryl¹),CO(aryl¹), OCO(aryl¹), OCO(heteroaryl¹), OCO(C₁₋₆ alkyl), OCOCH₂CN,CO₂(heteroaryl¹), CO₂(aryl¹), COCH₂(heteroaryl¹), S(O)_(n)aryl¹,S(O)_(n)CH₂aryl¹, S(O)_(n)(heteroaryl¹), S(O)_(n)CH₂(heteroaryl¹),NHSO₂aryl¹, NHSO₂(C₁₋₆ alkyl), NHSO₂(heteroaryl¹),NHSO₂CH₂(heteroaryl¹), NHSO₂CH₂(aryl¹), NHCOaryl¹, NHCO(C₁₋₆ alkyl),NHCONHaryl¹, NHCONH(C₁₋₆ alkyl), NHCOheteroaryl¹, NHCONHheteroaryl¹,NHCO₂(aryl¹), NHCO₂(C₁₋₆ alkyl), NHCO₂(heteroaryl¹), aryl²oxy,heteroaryl¹oxy, C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkyl, aryl,C₁₋₆ alkoxy, CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,C₂₋₆ alkanoyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy, CH₂(aryl¹),C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶, C₂₋₆ alkanoyloxy substitutedby C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy, CH₂(aryl¹), C₁₋₄ haloalkyl, halogen,OH, CN or NR²⁵R²⁶, cycloalkyl¹oxy, COcycloalkyl¹, heterocyclesubstituted by one or more substituent selected from C₁₋₆alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶,CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆ alkyl),CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl, aryloxy,aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl, heterocyclyloxysubstituted by one or more substituent selected from C₁₋₆alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶,CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆ alkyl),CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl, aryloxy,aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl, WHEREIN aryl¹ is phenyloptionally fused to a C₅₋₇ carbocyclic ring, which group is optionallysubstituted by one or more substituent selected from C₁₋₆alkyl(optionally substituted by OH, CN or halogen), C₁₋₆ haloalkoxy, OH,═O, NY²WY¹, halogen, C₁₋₆ alkoxy, CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶,NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), COaryl, COheteroaryl, SO₂NR²⁵R²⁶,S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl), S(O)_(n)(heteroaryl), CO₂(C₁₋₆alkyl), CO₂(aryl), CO₂(heteroaryl), CO₂H, (CH₂)₁₋₄CO₂(C₁₋₆ alkyl),(CH₂)₁₋₄CO₂H, (CH₂)₁₋₄CO₂(aryl), (CH₂)₁₋₄CO₂(heteroaryl),O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), O(CH₂)₁₋₄CO₂H, O(CH₂)₁₋₄CO₂(aryl),O(CH₂)₁₋₄CO₂(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH₂)oxy,aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶ and C₃₋₇ cycloalkyl, aryl² is phenyloptionally fused to a C₅₋₇ carbocyclic ring, which group is substitutedby one or more substituent selected from C₁₋₆ alkyl(substituted by OH),CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), COaryl,COheteroaryl, SO₂NR²⁵R²⁶, S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl),S(O)_(n)(heteroaryl), CO₂(C₁₋₆ alkyl), CO₂(aryl), CO₂(heteroaryl), CO₂H,(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), (CH₂)₁₋₄CO₂H, (CH₂)₁₋₄CO₂(aryl),(CH₂)₁₋₄CO₂(heteroaryl), O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), O(CH₂)₁₋₄CO₂H,O(CH₂)₁₋₄CO₂(aryl), O(CH₂)₁₋₄CO₂(heteroaryl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶ and C₃₋₇cycloalkyl, heteroaryl¹ is heteroaryl optionally fused to a C₅₋₇carbocyclic ring, which group is optionally substituted by one or moresubstituent selected from C₁₋₆ alkyl(optionally substituted by OH, CN orhalogen), C₁₋₆ haloalkoxy, OH, ═O, NY²WY¹, halogen, C₁₋₆ alkoxy,CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶, CO(C₁₋₆ alkyl), COaryl,COheteroaryl, SO₂NR²⁵R²⁶, S(O)_(n)(C₁₋₆ alkyl), S(O)_(n)(aryl),S(O)n(heteroaryl), CO₂(C₁₋₆ alkyl), CO₂(aryl), CO₂(heteroaryl), CO₂H,(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), (CH₂)₁₋₄CO₂H, (CH₂)₁₋₄CO₂(aryl),(CH₂)₁₋₄CO₂(heteroaryl), O(CH₂)₁₋₄CO₂(C₁₋₆ alkyl), O(CH₂)₁₋₄CO₂H,O(CH₂)₁₋₄CO₂(aryl), O(CH₂)₁₋₄CO₂(heteroaryl), aryl, heterocyclyl,aryloxy, aryl(CH₂)oxy, aryl(CH₂), CN, O(CH₂)₁₋₄CONR²⁵R²⁶ and C₃₋₇cycloalkyl, cycloalkyl¹ is a C₃₋₁₀ carbocyclic system with one or tworings and which is substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy,CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶, WITH THE PROVISOTHAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS A HETERO-ATOM LINKED TOANOTHER HETEROATOM VIA ONE SP3 CARBON Z is a direct bond, CO or S(O)_(n)group, B is (CH₂)_(p), R¹² and R¹³ each independently represent H orC₁₋₄ alkyl, or R¹² and R¹³ can be taken together with the N atom towhich they are attached to form a 4- to 7-membered heterocycleoptionally comprising a further hetero moiety selected from NR¹⁶, Oand/or S, and which is optionally substituted by one or more C₁₋₄ alkyl,R¹⁴ and R¹⁵ each independently represent H, C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl,C₃₋₁₀ alkynyl, C₃₋₈ cycloalkyl, aryl or heteroaryl, or R¹⁴ and R¹⁵ canbe taken together with the N atom to which they are attached to form a4- to 7-membered heterocycle optionally comprising a further heteromoiety selected from NR¹⁶, O and/or S, and which is optionallysubstituted by one or more C₁₋₄ alkyl, R¹⁶ is H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, (C₁₋₆ alkylene)(C₃₋₈ cycloalkyl) or (C₁₋₆ alkylene)aryl, R⁵and R⁸ when taken separately are each independently H, C₁₋₆ alkyl, R⁵and R⁸ can be taken together with the carbon atoms to which they arejoined to form a C₃₋₈ cycloalkyl ring, R⁶, R⁷, R⁹ and R¹⁰ when takenseparately are H, R⁵ and R⁶ or R⁷ can be taken together with the carbonatoms to which they are joined to form a C₃₋₈ cycloalkyl ring, X ishalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy, mis 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q is0 or 1; “Naturally occuring amino acid substituent” means the□-substituent that occurs in any one of the following natural aminoacids, glycine, alanine, valine, leucine, isoleucine, phenylalanine,tryptophan, tyrosine, histidine, serine, threonine, methionine,cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine,arginine or proline; “Heteroaryl” represents an aromatic ring containingup to four heteroatoms independently selected from N, O and S, and if aS atom is present in the ring, it can be present as part of a —S—, S(O)—or —S(O)₂— group, and which may be joined to the remainder of thecompound via any available atom(s); “Heterocycle” is a group containing1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selectedfrom N, O and S and up to 18 ring carbon atoms; “Aryl”, including in thedefinitions of “aryloxy”, etc., means a group comprising a phenyl ringand which may incorporate a further carbocyclic ring fused to saidphenyl ring and which may be joined to the remainder of the compound viaany available atom(s) (examples of such groups include naphthyl,indanyl, etc.); “Alkyl”, “alkenyl” and “alkynyl” groups can be linear orbranched if the number of carbon atoms allows; “Cycloalkyl” groups canbe polycyclic if the number of carbon atoms allows; or apharmaceutically or veterinarily acceptable derivative or prodrugthereof.
 2. A substance according to claim 1 wherein the “Ar” ringrepresents phenyl or pyridyl.
 3. A substance according to claim 1wherein R¹ when taken alone is OH, CN, halogen, NO₂, NH₂, NY²WY¹ orHet¹.
 4. A substance according to claim 1 wherein R² when taken alone isH.
 5. A substance according to claim 1 wherein R¹ and R² are takentogether with the carbon atoms to which they are attached and representan optionally benzo-fused 5- to 7-membered heteroaryl ring optionallysubstituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.
 6. A substance according toclaim 1 wherein X is Cl.
 7. A substance according to claim 1 wherein nis 0 and q is
 0. 8. A substance according claim 1 wherein R³ is H, CN,or C₁₋₆ alkyl (optionally substituted by one or more halogen, OH, C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₂₋₆ alkanoyloxy, C₂₋₆alkyloxycarbonyloxy, NR¹²R¹³, CONR¹²R¹³ and/or NY²WY¹).
 9. A substanceaccording to claim 1 wherein R⁴ is C₁₋₁₀ alkyl substituted by one ormore substituents selected from: C₂₋₆ alkoxy [substituted by one or moregroups selected from OH, NR²⁵ R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄alkynyl, C₂₋₄ alkenyl, heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹),CO(aryl¹), CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹),CO₂CH₂(aryl¹), CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl),S(O)_(n)(aryl¹), S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],S(O)_(n)C₁₋₆ alkyl [optionally substituted by one or more groupsselected from OH, NR²⁵R²⁶, CONR²⁵R²⁶, halogen, C₁₋₆ alkoxy, C₂₋₄alkynyl, C₂₋₄ alkenyl, heteroaryl¹, aryl¹, COCH₂CN, CO(heteroaryl¹),CO(aryl¹), CO₂(heteroaryl¹), COCH₂(aryl¹), COCH₂(heteroaryl¹),CO₂CH₂(aryl¹), CO₂CH₂(heteroaryl¹), S(O)_(n)(C₁₋₆ alkyl),S(O)_(n)(aryl¹), S(O)_(n)(heteroaryl¹), SO₂NR²⁵R²⁶ and cycloalkyl¹],aryl², CO₂CH₂(heteroaryl¹), CO₂CH₂(aryl¹), cycloalkyl¹, CO(heteroaryl¹),CO(aryl¹), OCO(aryl¹), OCO(heteroaryl¹), OCO(C₁₋₆ alkyl), OCOCH₂CN,CO₂(heteroaryl¹), CO₂(aryl¹), COCH₂(heteroaryl¹), S(O)_(n)aryl¹,S(O)_(n)CH₂aryl¹, S(O)_(n)(heteroaryl¹), S(O)_(n)CH₂(heteroaryl¹),NHSO₂aryl¹, NHSO₂(C₁₋₆ alkyl), NHSO₂(heteroaryl¹),NHSO₂CH₂(heteroaryl¹), NHSO₂CH₂(aryl¹), NHCOaryl¹, NHCO(C₁₋₆ alkyl),NHCONHaryl¹, NHCONH(C₁₋₆ alkyl), NHCOheteroaryl¹, NHCONHheteroaryl¹,NHCO₂(aryl¹), NHCO₂(C₁₋₆ alkyl), NHCO₂(heteroaryl¹), aryl²oxy,heteroaryl¹oxy, C₁₋₆ alkoxycarbonyl substituted by C₁₋₆ alkyl, aryl,C₁₋₆ alkoxy, CH₂(aryl¹), C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶,C₂₋₆ alkanoyl substituted by C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy, CH₂(aryl¹),C₁₋₄ haloalkyl, halogen, OH, CN or NR²⁵R²⁶, C₂₋₆ alkanoyloxy substitutedby C₁₋₆ alkyl, aryl, C₁₋₆ alkoxy, CH₂(aryl¹), C₁₋₄ haloalkyl, halogen,OH, CN or NR²⁵R²⁶, cycloalkyl¹ oxy, COcycloalkyl¹, heterocyclesubstituted by one or more substituent selected from C₁₋₆alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶,CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆ alkyl),CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl, aryloxy,aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl, heterocyclyloxysubstituted by one or more substituent selected from C₁₋₆alkyl(substituted by OH), CONR²⁵R²⁶, CH₂CONR²⁵R²⁶, NR²⁵R²⁶, NHCONR²⁵R²⁶,CO(C₁₋₆ alkyl), SO₂NR²⁵R²⁶, SO₂(C₁₋₆ alkyl), CO₂(C₁₋₆ alkyl),CH₂CO₂(C₁₋₆ alkyl), OCH₂CO₂(C₁₋₆ alkyl), aryl, heterocyclyl, aryloxy,aryl(CH₂)oxy, aryl(CH₂), CN and C₃₋₇ cycloalkyl,
 10. A substanceaccording to claim 1 wherein R⁵, R⁶, R⁷, R⁸ R⁹ and R¹⁰ are each takenseparately and are all H.
 11. A substance according claim 1 wherein the“Ar” ring represents a group of formula:


12. A substance according to claim 1 wherein R³ is H, CH₃, C₂H₅, i-C₃H₇,n-C₃H₇ or CH₂OCH₃.
 13. A substance according to claim 1 wherein R¹ isOH, CN, I, Cl, NH₂, NO₂, optionally benzo-fused heteroaryl, NHSO₂Y¹,NHCOY¹ or NHCO₂Y¹.
 14. A substance according to claim 1 wherein R⁴ isC₁₋₁₀ alkyl substituted by cycloalkyl¹.
 15. A substance according toclaim 1 except claims 3, 4 and 13 wherein R¹ and R² are taken togetherwith the carbon atoms to which they are attached are a 5-memberedheteroaryl moiety optionally substituted by C₁₋₄ alkyl or C₁₋₄haloalkyl.
 16. A substance according to claim 1 wherein R³is CH₃ orC₂H₅.
 17. A substance according to claim 1 except claims 5 and 15wherein R¹ when taken alone is OH, CN, I, Cl, NH₂, NO₂,1,2,3-triazolyl,1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl,benzimidazol-2-yl, NHSO₂(C₁₋₆ alkyl), NHSO₂(C₁₋₆ alkyl substituted bymethoxy, CONH₂, OH, CO₂(C₂₋₆ alkyl), phthalimido, NH₂ or halogen),NHSO₂NH₂, NHSO₂NH(C₁₋₆ alkyl), NHSO₂N(C₁₋₆ alkyl)₂, NHSO₂Het_(1a),NHCO(C₁₋₆ alkyl) or NHCO₂(C₁₋₆ alkyl).
 18. A substance according toclaim 17 wherein R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅, NHSO₂(n-C₃H₇),NHSO₂(i-C₃H₇), NHSO₂(n-C₄H₇), NHSO₂NH(i-C₃H₇),NHSO₂(N-methylimidazol-4-yl), NHSO₂(CH₂)₂OCH₃, NHSO₂(CH₂)₂OH,1,2,4-triazolyl or imidazol-2-yl.
 19. A substance according to claim 18wherein R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅ or imidazol-2-yl.
 20. A substanceaccording to claim 15 wherein R¹ and R² when taken together with thecarbon atoms to which they are attached are an imidazole groupoptionally 2-substituted by CF₃.
 21. A substance according to claim 1wherein R⁴ is C₂₋₄ alkyl substituted by cycloalkyl¹.
 22. A substanceaccording to claim 1 wherein R⁴ is propyl substituted by cycloalkyl¹.23. A substance according to claim 1 wherein R⁴ is propyl substituted bya C₃₋₁₀ carbocyclic system with one or two rings and which issubstituted by OH.
 24. A substance according to claim 1 wherein R⁴ ispropyl substituted by (cyclohexyl substituted by OH).
 25. A substanceaccording to claim 1 wherein R⁴ is (1-hydroxycyclohexyl)prop-3-yl.
 26. Asubstance according to claim 1 which has the following relativestereochemistry:


27. A pharmaceutical or veterinary composition comprising a substanceaccording to claim 1, and a pharmacutically or veterinarily acceptablecarrier.
 28. A method of treatment of a condition mediated by an opiatereceptor or receptors comprising administration of a therapeuticallyactive amount of a substance according to claim
 1. 29. A process for thepreparation of a substance of formula I which comprises: (a) forcompounds of formula I in which q is 0 and R¹ represents NY²WY¹,reacting a compound of formula II,

 with a compound of formula III, Z¹-WY¹  III wherein Z¹ is a suitableleaving group, such as halogen or Y¹SO₂O—; (b) for compounds of formulaI in which q is 0 and R⁶ and R⁷ both represent H, reduction of acompound of formula IV,

 using a suitable reducing agent; (c) for compounds of formula I inwhich q is 0 and R⁹ and R¹⁰ both represent H, reduction of a compound offormula V,

 using a suitable reducing agent; (d) for compounds of formula I inwhich q is 0 and R¹ and R² are attached to adjacent carbon atoms and aretaken together with the carbon atoms to which they are attached torepresent Het^(1a), in which Het^(1a) represents an imidazolo unit,reaction of a corresponding compound of formula VI,

 with a compound of formula VII, R^(y)CO₂H  VII wherein R^(y) representsH or any of the optional substituents on Het^(1a) (as defined above),preferably H, C₁₋₄ alkyl or C₁₋₄ haloalkyl; (e) where q is 0, reacting acompound of formula VIII,

 with a compound of formula IX, R⁴-Lg  IX wherein Lg is a leaving group;(f) for compounds of formula I in which q is 0 and R⁶, R⁷, R⁹ and R¹⁰are all H, reduction of a compound of formula X,

 with a suitable reducing agent; (g) for compounds of formula I in whichq is 0 and R¹ represents OH, reacting a compound of formula II, where Y²is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h)for compounds of formula I in which q is 0 and R¹ represents Cl,reacting a compound of formula II, where Y² is H, as defined above, withsodium nitrite in the presence of dilute acid, followed by reaction withcopper (I) chloride in the presence of concentrated acid; (i) forcompounds of formula I in which q is 1, reacting a compound of formula Iwhere q is 0 with a suitable oxidising agent such as aqueous hydrogenperoxide; or (j) for compounds of formula I where q is 0, by reductionof a corresponding compound of formula XXXI,

where R^(4a)CH₂ takes the same meaning as R⁴ as defined above, (K) forcompounds of formula (I) where q is 0, reductive amination reaction ofthe amine of formula VIII above with an aldehyde of formula R^(4a)—CHOwherein R^(4a)CH₂ takes the same meaning as R⁴ as defined above, andwhere desired or necessary converting the resulting compound of formulaI into a pharmaceutically or veterinarily acceptable derivative or viceversa.
 30. A compound of formula II, IV, V, VI, X, X^(a), XI, XII, XXI,XXII, XXIII, XXIV, XXIX, XXIXa, XXX, or XXXI, or salt thereof, asdescribed herein.